Characterization and pharmacokinetic parameters of recombinant soluble interleukin-4 receptor.
The interleukin-4 receptor (IL-4R) is expressed as a 140-Kd membrane glycoprotein that binds IL-4 with high affinity. Recently, cDNA clones for the murine IL-4R have been isolated. One clone encodes an integral membrane protein, while another encodes a protein in which translation is terminated before the transmembrane region, thus producing a soluble form of the IL-4R (sIL-4R). HeLa cell clones overexpressing sIL-4R were isolated using a novel filter-overlay and 125I-IL-4 ligand binding technique. Quantitative analysis demonstrated that the kinetics and affinity of IL-4 binding to the recombinant sIL-4R were similar to the native membrane-bound IL-4R. As low doses of sIL-4R specifically inhibited IL-4-induced proliferative responses in vitro, sIL-4R biodistribution and elimination parameters were evaluated to assess the pharmacokinetic potential of sIL-4R as a therapeutic agent. Pharmacokinetic studies demonstrated that radiolabeled sIL-4R had a distribution half-life of 9 minutes and an elimination half-life of 2.3 hours following intravenous (IV) administration. When administered by intraperitoneal or subcutaneous (SC) injection, the elimination half-lives were prolonged to 4.2 hours and 6.2 hours, respectively. Although the initial blood level of sIL-4R was reduced if administered by SC injection, the bioavailability was comparable with IV administration. The main sites of sIL-4R elimination were the liver and kidney.
Jacobs
C A
CA
Immunex Corporation, Seattle, WA 98101.
Lynch
D H
DH
Roux
E R
ER
Miller
R
R
Davis
B
B
Widmer
M B
MB
Wignall
J
J
VandenBos
T
T
Park
L S
LS
Beckmann
M P
MP
D000818:Animals; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D006367:HeLa Cells / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014018:Tissue Distribution
D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D011994:Recombinant Proteins; D015847:Interleukin-4