Structural optimization of a TNFR1-selective antagonistic TNFα mutant to create new-modality TNF-regulating biologics
Autor: | Haruhiko Kamada, Yasuo Tsutsumi, Kanako Yamashita, Natsuki Osaki, Masaki Inoue, Masahiro Kunishige, Shota Amano, Yuki Morita, Yuta Tsuji, Shota Enomoto, Chinatsu Yoshimine, Shin-ichi Tsunoda, Midori Miki |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Recombinant Fusion Proteins medicine.medical_treatment Immunology Mutation Missense Arthritis T-Lymphocytes Regulatory Biochemistry Cell Line Proinflammatory cytokine Etanercept Mice 03 medical and health sciences Immune system medicine Animals Molecular Biology Autoimmune disease Mice Inbred BALB C 030102 biochemistry & molecular biology Tumor Necrosis Factor-alpha business.industry Cell Biology respiratory system medicine.disease Immunoglobulin Fc Fragments TNF inhibitor 030104 developmental biology Cytokine Amino Acid Substitution Receptors Tumor Necrosis Factor Type I Immunoglobulin G Cancer research Tumor necrosis factor alpha business medicine.drug |
Zdroj: | J Biol Chem |
ISSN: | 0021-9258 |
Popis: | Excessive activation of the proinflammatory cytokine tumor necrosis factor-α (TNFα) is a major cause of autoimmune diseases, including rheumatoid arthritis. TNFα induces immune responses via TNF receptor 1 (TNFR1) and TNFR2. Signaling via TNFR1 induces proinflammatory responses, whereas TNFR2 signaling is suggested to suppress the pathophysiology of inflammatory diseases. Therefore, selective inhibition of TNFR1 signaling and preservation of TNFR2 signaling activities may be beneficial for managing autoimmune diseases. To this end, we developed a TNFR1-selective, antagonistic TNFα mutant (R1antTNF). Here, we developed an R1antTNF derivative, scR1antTNF-Fc, which represents a single-chain form of trimeric R1antTNF with a human IgG-Fc domain. scR1antTNF-Fc had properties similar to those of R1antTNF, including TNFR1-selective binding avidity, TNFR1 antagonistic activity, and thermal stability, and had a significantly extended plasma t(1/2) in vivo. In a murine rheumatoid arthritis model, scR1antTNF-Fc and 40-kDa PEG-scR1antTNF (a previously reported PEGylated form) delayed the onset of collagen-induced arthritis, suppressed arthritis progression in mice, and required a reduced frequency of administration. Interestingly, with these biologic treatments, we observed an increased ratio of regulatory T cells to conventional T cells in lymph nodes compared with etanercept, a commonly used TNF inhibitor. Therefore, scR1antTNF-Fc and 40-kDa PEG-scR1antTNF indirectly induced immunosuppression. These results suggest that selective TNFR1 inhibition benefits the management of autoimmune diseases and that R1antTNF derivatives hold promise as new-modality TNF-regulating biologics. |
Databáze: | OpenAIRE |
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