The treatment of established murine collagen-induced arthritis with a TNFR1-selective antagonistic mutant TNF

Abstract

Blocking the binding of TNF-α 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-β 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.