The treatment of established murine collagen-induced arthritis with a TNFR1-selective antagonistic mutant TNF.
Blocking the binding of TNF-alpha to TNF receptor subtype-1 (TNFR1) is an important strategy for the treatment of rheumatoid arthritis (RA). We recently succeeded in developing a TNFR1-selective antagonistic TNF mutant, R1antTNF. Here, we report the anti-inflammatory effects of R1antTNF in a murine collagen-induced arthritis model. To improve the in vivo stability of R1antTNF, we first engineered PEG (polyethylene glycol)-modified R1antTNF (PEG-R1antTNF). In prophylactic protocols, PEG-R1antTNF clearly improved the incidence, and the clinical score of arthritis due to its long plasma half-life. Although, the effect of PEG-R1antTNF on the incidence and production of IL1-beta was less than that of the existing TNF-blocking drug Etanercept, its effect on severity was almost as marked as Etanercept. Interestingly, in therapeutic protocols, PEG-R1antTNF showed greater therapeutic effect than Etanercept. These data suggest that the anti-inflammatory effects of PEG-R1antTNF depend on the stage of arthritis. Recently, there has been much concern over the reactivation of viral infection caused by TNF blockade. Unlike Etanercept, PEG-R1antTNF did not reactivate viral infection. Together, these results indicate that selective inhibition of TNF/TNFR1 could be effective in treating RA and that PEG-R1antTNF could serve as a promising anti-inflammatory drug for this purpose.
Shibata
Hiroko
H
Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation (NIBIO), Ibaraki, Osaka 567-0085, Japan.
Yoshioka
Yasuo
Y
Abe
Yasuhiro
Y
Ohkawa
Akiko
A
Nomura
Tetsuya
T
Minowa
Kyoko
K
Mukai
Yohei
Y
Nakagawa
Shinsaku
S
Taniai
Madoka
M
Ohta
Tsunetaka
T
Kamada
Haruhiko
H
Tsunoda
Shin-ichi
S
Tsutsumi
Yasuo
Y
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D049109:Cell Proliferation; D003094:Collagen / Q000633:toxicity*; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D010010:Osteoclasts / Q000166:cytology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors*; D020349:Surface Plasmon Resonance; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*
D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen