title: Evaluation of recombinant human soluble dimeric tumor necrosis factor receptor for prevention of OKT3-associated acute clinical syndrome.
abstract: Tumor necrosis factor alpha (TNFa) has been shown to be the primary cytokine responsible for the OKT3-induced acute clinical syndrome (OKT3-ACS). Recombinant human soluble tumor necrosis factor receptor (TNFR:Fc) is a dimer of the p80 TNF receptor, which binds both TNFa and lymphotoxin (LT). Renal allograft recipients undergoing OKT3 therapy for steroid-resistant rejection were randomized to receive OKT3 alone or in combination with TNFR:Fc to determine its safety and efficacy in decreasing 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 injections of OKT3. All patients were monitored for manifestations of OKT3-ACS and changes in renal function. In addition, serial serum samples were assayed for TNFa and TNFR:Fc levels (ELISA) and TNFa bioactivity (L929). No adverse side effects were identified in patients receiving TNFR:Fc. Patients treated with TNFR:Fc had significantly fewer symptoms by day 2 of OKT3, and had a lower overall incidence of chills and arthralgias. Renal dysfunction reversed within 24 hr in the TNFR:Fc-treated group in contrast to the 48-72-hr delay in the control group. Antigenic 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 pretreatment 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 the day 1 samples from TNFR:Fc-treated patients, whereas significant bioactivity (peak mean 60 +/- 35 pg/ml) was detected in sera from control patients. TNF receptor levels reached 600 ng/ml in treated patients and 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 tolerated and may limit the severity of OKT3-ACS. The most significant observation was a more rapid improvement in renal function in the TNFR:Fc-treated 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.
authors.affiliation: Transplantation Unit, Massachusetts General Hospital, Boston, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Eason
authors.forename: M
authors.initials: M
authors.lastname: Pascual
authors.forename: S
authors.initials: S
authors.lastname: Wee
authors.forename: M
authors.initials: M
authors.lastname: Farrell
authors.forename: J
authors.initials: J
authors.lastname: Phelan
authors.forename: S
authors.initials: S
authors.lastname: Boskovic
authors.forename: C
authors.initials: C
authors.lastname: Blosch
authors.forename: K M
authors.initials: KM
authors.lastname: Mohler
authors.forename: A B
authors.initials: AB
authors.lastname: Cosimi
mesh_terms: D000208:Acute Disease; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016030:Kidney Transplantation; D016853:Muromonab-CD3 / Q000009:adverse effects*; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000627:therapeutic use; D013577:Syndrome; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D016853:Muromonab-CD3; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins