Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 28, Pages 9379-9391Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.012723
Keywords
tumor necrosis factor (TNF); cytokine; autoimmune disease; arthritis; inflammation; inhibition mechanism; protein engineering; drug design; drug delivery; forkhead box P3 (FOXP3); antagonist; single-chain
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Funding
- JSPS KAKENHI [JP18K14877, JP18H02699, JP18K19567]
- Takeda Science Foundation
- Mochida Memorial Foundation forMedical and Pharmaceutical Research
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Excessive activation of the proinflammatory cytokine tumor necrosis factor-alpha (TNF alpha) is a major cause of autoimmune diseases, including rheumatoid arthritis. TNF alpha 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 TNF alpha 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.
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