title: Characterization and pharmacokinetic parameters of recombinant soluble interleukin-4 receptor.
abstract: 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.
authors.affiliation: Immunex Corporation, Seattle, WA 98101.
authors.forename: C A
authors.initials: CA
authors.lastname: Jacobs
authors.forename: D H
authors.initials: DH
authors.lastname: Lynch
authors.forename: E R
authors.initials: ER
authors.lastname: Roux
authors.forename: R
authors.initials: R
authors.lastname: Miller
authors.forename: B
authors.initials: B
authors.lastname: Davis
authors.forename: M B
authors.initials: MB
authors.lastname: Widmer
authors.forename: J
authors.initials: J
authors.lastname: Wignall
authors.forename: T
authors.initials: T
authors.lastname: VandenBos
authors.forename: L S
authors.initials: LS
authors.lastname: Park
authors.forename: M P
authors.initials: MP
authors.lastname: Beckmann
mesh_terms: 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
chemical_list: D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D011994:Recombinant Proteins; D015847:Interleukin-4