title: TNF receptor II fusion protein with tandemly repeated Fc domains.
abstract: The extracellular domain of tumour necrosis factor (TNF) receptor II fused with the human IgG1 Fc region (TNFRII-Fc), as well as antibodies against TNF, has been used to treat rheumatoid arthritis. However, TNFRII-Fc is less effective than these antibodies in terms of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against cells bearing TNF on the cell surface. We hypothesized that these activities could be increased by fusing TNFRII with tandemly repeated Fc (TNFRII-Fc-Fc). The affinities of TNFRII-Fc-Fc for soluble TNF-α and transmembrane TNF-α and the TNF-α cytotoxicity-inhibitory activity were as potent as those of TNFRII-Fc. TNFRII-Fc-Fc showed much higher binding avidity for Fcγ receptors than TNFRII-Fc and was more potent in terms of both ADCC and CDC against cells expressing transmembrane TNF-α. TNFRII-Fc-Fc of 80 kDa, as well as TNFRII-Fc-Fc of 200 kDa, was detected. TNFRII-Fc-Fc (80 kDa) was as potent as TNFRII-Fc in terms of both ADCC and CDC. These results suggest that Fc multimerization of receptor-Fc fusion proteins can augment effector functions such as ADCC and CDC, and thereby have the potential to provide a superior therapeutic effect. This may be the case not only for TNFRII-Fc but also for other receptor-Fc fusion proteins.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda, Chiba, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagashima
authors.forename: Kaname
authors.initials: K
authors.lastname: Kaneko
authors.forename: Ayaka
authors.initials: A
authors.lastname: Yamanoi
authors.forename: Sotaro
authors.initials: S
authors.lastname: Motoi
authors.forename: Shu
authors.initials: S
authors.lastname: Konakahara
authors.forename: Junya
authors.initials: J
authors.lastname: Kohroki
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Masuho
mesh_terms: D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007141:Immunoglobulin Fc Fragments; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins