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

Autor: Amer Abouhamze, Jill Gasser, Lyle L. Moldawer, J. Frazier, Tadahiko Kohno, Angela Nelson, Carl K. Edwards, Steven W. Martin, William J. Boyle, James Ervin Seely, Olaf B Kinstler, Gary L. Kieft, Jeff Rose, Jason J. Rosenberg, Kunitaro Fukuzuka, William Marshall, Gregory C. Gaines, Ulrich Feige, Judy St. Clair
Rok vydání: 2001
Předmět:
Zdroj: Journal of Applied Physiology. 91:2213-2223
ISSN: 1522-1601
8750-7587
DOI: 10.1152/jappl.2001.91.5.2213
Popis: Pharmacokinetics and immunogenicity of six different recombinant human soluble p55 tumor necrosis factor (TNF) receptor I (sTNFR-I) constructs were evaluated in juvenile baboons. The constructs included either an sTNFR-I IgG1 immunoadhesin (p55 sTNFR-I Fc) or five different sTNFR-I constructs covalently linked to polyethylene glycol. The constructs were administered intravenously 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-α-induced mortality, baboons were pretreated with 1, 5, or 10 mg/kg body wt and were 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 colibacteremia. The monomeric construct protected baboons and neutralized TNF bioactivity, although greater quantities were required compared with the dimeric 4.0-domain sTNFR-I construct. We conclude that E. coli-recombinant-derived human sTNFR-I constructs can be generated with minimal immunogenicity on repeated administration and still protect against the consequences of exaggerated TNF-α production.
Databáze: OpenAIRE