Back to Search
Start Over
Anti-Tumor Necrosis Factor With a Glyco-Engineered Fc-Region Has Increased Efficacy in Mice With Colitis
- Source :
- Gastroenterology, 153(5), 1351, Gastroenterology, 153(5), 1351-1362.e4. W.B. Saunders Ltd
- Publication Year :
- 2017
-
Abstract
- 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 Fcγ receptors (FcγR), and whether the absence of the Fc core fucose (which increases binding to FcγRIIIa) increases the efficacy of anti-TNF in mice with colitis. Methods We generated Rag1 −/− mice that lack all activating FcγRs (FcγRI, FcγRIII, and FcγRIV; called FcγR −/− 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 FcγR −/− 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 FcγRIIIa-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, FcγR −/− Rag1 −/− mice were refractory to the effects of anti-TNF: their histological colitis scores were as severe as those from FcγR −/− 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 FcγR −/− Rag1 −/− mice given anti-TNF these numbers were as low as FcγR −/− Rag1 −/− given the control antibody. In human PBMCs, anti-TNF increased the number of CD206 + macrophages: this required expression of FcγRIIIa; numbers of these cells were reduced in PBMCs with the low-affinity FcγRIIIa-158F genotype. A hypo-fucosylated form of adalimumab bound human FcγRIIIa 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 FcγRIIIa. 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 FcγR 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 FcγRIIIa with higher affinity and induces development of CD206 + macrophages in human PBMCs, especially PBMCs that express low-affinity FcγRIIIa. Hypo-fucosylated anti-TNF might be more effective in patients with inflammatory bowel disease.
- Subjects :
- 0301 basic medicine
Time Factors
T-Lymphocytes
Lymphocyte
Crohn's Disease
Lymphocyte Activation
Inflammatory bowel disease
Intestinal Mucosa
Cells, Cultured
Mice, Knockout
Antibody-dependent cell-mediated cytotoxicity
biology
Gastroenterology
Antibodies, Monoclonal
Colitis
Adoptive Transfer
Isotype
Phenotype
medicine.anatomical_structure
Tumor necrosis factor alpha
Antibody
Immunosuppressive Agents
Mannose Receptor
Colon
medicine.drug_class
Fc gamma Receptor
Receptors, Cell Surface
Monoclonal antibody
03 medical and health sciences
medicine
Drug Modification
Animals
Genetic Predisposition to Disease
Lectins, C-Type
Cell Proliferation
Homeodomain Proteins
Wound Healing
Mouse Model
Hepatology
Tumor Necrosis Factor-alpha
business.industry
Macrophages
Receptors, IgG
Adalimumab
medicine.disease
Molecular biology
Mice, Inbred C57BL
Disease Models, Animal
Mannose-Binding Lectins
030104 developmental biology
Immunology
biology.protein
business
Subjects
Details
- Language :
- English
- ISSN :
- 00165085
- Database :
- OpenAIRE
- Journal :
- Gastroenterology, 153(5), 1351, Gastroenterology, 153(5), 1351-1362.e4. W.B. Saunders Ltd
- Accession number :
- edsair.doi.dedup.....d77f0e1d97959e93ec6c7b37d643c8aa