Journal of Applied Physiology
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J Appl Physiol 84: 1119-1130, 1998;
8750-7587/98 $5.00
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Vol. 84, Issue 4, 1119-1130, April 1998

Pharmacokinetics, immunogenicity, and efficacy of dimeric TNFR binding proteins in healthy and bacteremic baboon

Carmen C. Solorzano1, Atsushi Kaibara1, Phillip J. Hess1, Paul D. Edwards1, Riadh Ksontini1, Amer Abouhamze1, Sherry McDaniel1, Janet Frazier2, Deborah Trujillo2, Gary Kieft2, James Seely2, Tadahiko Kohno2, Mary Ellen Cosenza2, Michael Clare-Salzler3, Sally L. D. MacKay1, Steven W. Martin4, Lyle L. Moldawer1, and Carl K. Edwards III2

1 Departments of Surgery and 3 Pathology, University of Florida College of Medicine, Gainesville, Florida 32610; 2 Amgen, Inc., Boulder, Colorado 80301; and 4 Amgen, Inc., Thousand Oaks, California 91320

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.

tumor necrosis factor receptor; sepsis; baboons; antibodies


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