EVALUATION OF RECOMBINANT HUMAN SOLUBLE DIMERIC TUMOR-NECROSIS-FACTORRECEPTOR FOR PREVENTION OF OKT3-ASSOCIATED ACUTE CLINICAL SYNDROME

Tumor necrosis factor alpha (TNFa) has been shown to be the primary cy tokine responsible for the OKT3-induced acute clinical syndrome (OKT3- ACS). Recombinant human soluble tumor necrosis factor receptor (TNFR:F c) is a dimer of the p80 TNF receptor, which binds both TNFa and lymph otoxin (LT), Renal allograft recipients undergoing OKT3 therapy for st eroid-resistant rejection were randomized to receive OKT3 alone or in combination with TNFR:Fc to determine its safety and efficacy in decre asing the severity of OKT3-ACS and in restoring renal function, Six of 12 patients were given TNFR:Fc prior to each of the first two injecti ons of OKT3. All patients were monitored for manifestations of OKT3-AC S and changes in renal function. In addition, serial serum samples wer e assayed for TNFa and TNFR:Fc levels (ELISA) and TNFa bioactivity (L9 29). No adverse side effects were identified in patients receiving TNF R:Fc. Patients treated with TNFR:Fc had significantly fewer symptoms b y day 2 of OKT3, and had a lower overall incidence of chills and arthr algias. Renal dysfunction reversed within 24 hr in the TNFR:Fc-treated group in contrast to the 48-72-hr delay in the control group, Antigen ic TNFa levels increased in the control group from <10 pg/ml pre OKT3 to a mean peak level of 30+/-13 pg/ml on day 1 and decreased to pretre atment levels by day 2, TNFR:Fc-treated patients had a mean peak TNFa level of 235+/-135 pg/ml, suggesting a carrier effect of TNFR: Fc, In contrast, bioactivity was barely detectable (mean 20+/-14 pg/ml) in th e day 1 samples from TNFR: Fc-treated patients, whereas significant bi oactivity (peak mean 60+/-35 pg/ml) was detected in sera from control patients, TNF receptor levels reached 600 ng/ml in treated patients an d remained elevated for up to 18 days confirming the long half-life of TNFR:Fc, This phase 1 trial demonstrates that TNFR:Fc is well tolerat ed and may limit the severity of OKT3-ACS, The most significant observ ation was a more rapid improvement in renal function in the TNFR:Fc-tr eated patients. The absence of TNFa bioactivity indicates that TNFR:Fc functions as a TNF antagonist. Further evaluation of higher doses of TNFR:Fc in OKT3-treated patients is currently in progress.