title: Characterization and favorable in vivo properties of heterodimeric soluble IL-15·IL-15Rα cytokine compared to IL-15 monomer.
abstract: Interleukin-15 (IL-15), a 114-amino acid cytokine related to IL-2, regulates immune homeostasis and the fate of many lymphocyte subsets. We reported that, in the blood of mice and humans, IL-15 is present as a heterodimer associated with soluble IL-15 receptor α (sIL-15Rα). Here, we show efficient production of this noncovalently linked but stable heterodimer in clonal human HEK293 cells and release of the processed IL-15·sIL-15Rα heterodimer in the medium. Purification of the IL-15 and sIL-15Rα polypeptides allowed identification of the proteolytic cleavage site of IL-15Rα and characterization of multiple glycosylation sites. Administration of the IL-15·sIL-15Rα heterodimer reconstituted from purified subunits resulted in sustained plasma IL-15 levels and in robust expansion of NK and T cells in mice, demonstrating pharmacokinetics and in vivo bioactivity superior to single chain IL-15. These identified properties of heterodimeric IL-15 provide a strong rationale for the evaluation of this molecule for clinical applications.
authors: AIDS and Cancer Virus Program, SAIC-Frederick Inc., Frederick National Laboratory, Frederick, Maryland 21702, USA.
authors: Elena
authors: E
authors: Chertova
authors: Cristina
authors: C
authors: Bergamaschi
authors: Oleg
authors: O
authors: Chertov
authors: Raymond
authors: R
authors: Sowder
authors: Jenifer
authors: J
authors: Bear
authors: James D
authors: JD
authors: Roser
authors: Rachel K
authors: RK
authors: Beach
authors: Jeffrey D
authors: JD
authors: Lifson
authors: Barbara K
authors: BK
authors: Felber
authors: George N
authors: GN
authors: Pavlakis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D019409:Interleukin-15 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D011485:Protein Binding; D055503:Protein Multimerization; D059748:Proteolysis; D012995:Solubility; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
chemical_list: D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D046912:Multiprotein Complexes
keywords: CD8+ T Cells; Glycosylation; HEK293 Human Cell; HPLC; Heterodimeric Cytokine; Interleukin; Interleukin-15; Natural Killer (NK) Cell; Proteolytic Cleavage; T Cell
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