PHARMACOKINETICS, IMMUNOGENICITY, AND EFFICACY OF DIMERIC TNFR BINDING-PROTEINS IN HEALTHY AND BACTEREMIC BABOON

Immunogenicity, pharmacokinetics, and therapeutic efficacy of three no vel dimeric soluble tumor necrosis factor (TNF)receptor I constructs [ TNF-binding protein (bp)] were evaluated in 28 baboons, 12 of which we re healthy and 16 were challenged with a lethal Escherichia coli bacte remia. The three constructs differed only in the number of extracellul ar domains of the TNF receptor I and were dimerized with polyethylene glycol. Although all three constructs had generally similar pharmacoki netics when administered to a naive animal, they differed quantitative ly in their immunogenicity. Antibodies were detected more frequently, and titers were significantly higher (P < 0.05) in both healthy and se ptic baboons that received the 4.0-domain TNF-bp construct, compared w ith animals receiving the 2.6-domain construct. When the TNF-bp constr ucts were administered a second time (21 days later), the half-lives o f the three constructs were significantly shorter in animals that had an antibody response after the first injection. In contrast, all three TNF-bp constructs were equally effective at improving outcome, blocki ng a systemic TNF-alpha response, and attenuating the cytokine respons es when administered at a dose of 1.0 mg/kg body wt 1 h before a letha l E. coli infusion. The findings suggest that immunogenicity of TNF-bp constructs can be altered by changing the number of functional domain s, without affecting their capacity to neutralize TNF-alpha and to abr ogate TNF-mediated pathology.