Pharmacokinetics, immunogenicity, and efficacy of dimeric TNFR binding proteins in healthy and bacteremic baboon.
J Appl Physiol (1985)
; 84(4): 1119-30, 1998 Apr.
Article
em En
| MEDLINE
| ID: mdl-9516174
ABSTRACT
Immunogenicity, pharmacokinetics, and therapeutic efficacy of three novel dimeric soluble tumor necrosis factor (TNF)-receptor I constructs [TNF-binding protein (bp)] were evaluated in 28 baboons, 12 of which were healthy and 16 were challenged with a lethal Escherichia coli bacteremia. The three constructs differed only in the number of extracellular domains of the TNF receptor I and were dimerized with polyethylene glycol. Although all three constructs had generally similar pharmacokinetics when administered to a naive animal, they differed quantitatively in their immunogenicity. Antibodies were detected more frequently, and titers were significantly higher (P < 0.05) in both healthy and septic baboons that received the 4.0-domain TNF-bp construct, compared with animals receiving the 2.6-domain construct. When the TNF-bp constructs were administered a second time (21 days later), the half-lives of 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, blocking a systemic TNF-alpha response, and attenuating the cytokine responses when administered at a dose of 1.0 mg/kg body wt 1 h before a lethal E. coli infusion. The findings suggest that immunogenicity of TNF-bp constructs can be altered by changing the number of functional domains, without affecting their capacity to neutralize TNF-alpha and to abrogate TNF-mediated pathology.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Bacteriemia
/
Receptores do Fator de Necrose Tumoral
/
Infecções por Escherichia coli
Limite:
Animals
Idioma:
En
Revista:
J Appl Physiol (1985)
Assunto da revista:
FISIOLOGIA
Ano de publicação:
1998
Tipo de documento:
Article
País de afiliação:
Estados Unidos