Pharmacokinetics, immunogenicity, and efficacy of dimeric TNFR binding proteins in healthy and bacteremic baboon.
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.
Solorzano
C C
CC
Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Kaibara
A
A
Hess
P J
PJ
Edwards
P D
PD
Ksontini
R
R
Abouhamze
A
A
McDaniel
S
S
Frazier
J
J
Trujillo
D
D
Kieft
G
G
Seely
J
J
Kohno
T
T
Cosenza
M E
ME
Clare-Salzler
M
M
MacKay
S L
SL
Martin
S W
SW
Moldawer
L L
LL
Edwards
C K
CK
D000818:Animals; D000917:Antibody Formation / Q000502:physiology; D016470:Bacteremia / Q000276:immunology* / Q000473:pathology; D018360:Crystallography, X-Ray; D004927:Escherichia coli Infections / Q000276:immunology* / Q000473:pathology; D005260:Female; D006207:Half-Life; D007074:Immunoglobulin G / Q000096:biosynthesis; D007668:Kidney / Q000473:pathology; D007700:Kinetics; D007958:Leukocyte Count; D008297:Male; D008968:Molecular Conformation; D010215:Papio; D011485:Protein Binding; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology* / Q000378:metabolism*
D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor