Development of a novel, nonimmunogenic, soluble human TNF receptor type I (sTNFR-I) construct in the baboon

Pharmacokinetics and immunogenicity of six different recombinant human solu ble p55 tumor necrosis factor (TNF) receptor I (sTNFR-I) constructs were ev aluated in juvenile baboons. The constructs included either an sTNFR-I IgG1 immunoadhesin (p55 sTNFR-I Fc) or five different sTNFR-I constructs covale ntly linked to polyethylene glycol. The constructs were administered intrav enously three times, and pharmacokinetics and immunogenicity were examined over 63 days. All of the constructs were immunogenic, with the exception of a 2.6-domain monomeric sTNFR-I. To evaluate whether the nonimmunogenic 2.6 -domain monomeric construct could protect baboons against TNF-alpha -induce d mortality, baboons were pretreated with 1, 5, or 10 mg/kg body wt and wer e compared with baboons receiving either placebo or 1 mg/kg body wt of the dimeric 4.0-domain sTNFR-I construct (n = 3 each) before lethal Escherichia coli bacteremia. The monomeric construct protected baboons and neutralized TNF bioactivity, although greater quantities were required compared with t he dimeric 4.0-domain sTNFR-I construct. We conclude that E. coli-recombina nt-derived human sTNFR-I constructs can be generated with minimal immunogen icity on repeated administration and still protect against the consequences of exaggerated TNF-alpha production.