title: Use of an antibody against the soluble interleukin 2 receptor alpha subunit can modulate the stability and biodistribution of interleukin-2.
abstract: The authors have previously reported that the soluble serum form of the alpha subunit of the IL-2 receptor (sIL-2Ralpha), whose natural half-life is approximately 40 min, survived much longer in the circulation when bound by a specific antibody. In the present study, the authors evaluated the extent to which sIL-2Ralpha protected IL-2 in freshly collected serum using biochemical analyses, and a functional CTLL-2 assay. In particular, sIL-2Ralpha protected IL-2 from forming complexes with alpha(2)-macroglobulin and from inactivation in vitro. In addition, the authors demonstrated that the anti-IL-2Ralpha monoclonal antibody 7G7/B6, which does not inhibit the binding of IL-2 to its binding site on sIL-2Ralpha, protected IL-2 from degradation and inactivation in vivo in the presence of sIL-2Ralpha. Both(125)I-labelled and unlabelled IL-2 were injected into mice preinjected with humanized anti-Tac (hTac) or 7G7/B6 and sIL-2Ralpha, or sIL-2Ralpha alone. Using size-exclusion HPLC, ELISA, and CTLL-2 cell proliferation assays, we observed that the presence of 7G7/B6 led to formation of complexes with sIL-2Ralpha and increased the serum levels of IL-2 more than 3- to 40-fold those of groups receiving IL-2 alone, sIL-2Ralpha, or hTac. Taken as a whole, these results suggest that the complex of 7G7/B6 and sIL-2Ralpha not only prolongs the survival of IL-2 in vivo, but also maintains the bioactivity of IL-2. The use of antibodies against endogenous soluble receptors could increase the in vivo survival of cytokines, protect their bioactivity and thereby facilitate their clinical use in the treatment of various malignancies and AIDS.
authors.affiliation: Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, USA. hisataka@kuhp.kyoto-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Tagaya
authors.forename: E S
authors.initials: ES
authors.lastname: Han
authors.forename: I S
authors.initials: IS
authors.lastname: Kim
authors.forename: N
authors.initials: N
authors.lastname: Le
authors.forename: C H
authors.initials: CH
authors.lastname: Paik
authors.forename: I
authors.initials: I
authors.lastname: Pastan
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: T A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: J A
authors.initials: JA
authors.lastname: Carrasquillo
mesh_terms: D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000097:blood* / Q000276:immunology*; D011485:Protein Binding; D015375:Receptors, Interleukin-2 / Q000097:blood* / Q000276:immunology*; D000511:alpha-Macroglobulins / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D000511:alpha-Macroglobulins