title: IL-13 antibodies influence IL-13 clearance in humans by modulating scavenger activity of IL-13Rα2.
abstract: Human studies using Abs to two different, nonoverlapping epitopes of IL-13 suggested that epitope specificity can have a clinically significant impact on clearance of IL-13. We propose that Ab modulation of IL-13 interaction with IL-13Rα2 underlies this effect. Two Abs were administered to healthy subjects and mild asthmatics in separate dose-ranging studies and allergen-challenge studies. IMA-638 allows IL-13 interaction with IL-13Rα1 or IL-13Rα2 but blocks recruitment of IL-4Rα to the IL-13/IL-13Rα1 complex, whereas IMA-026 competes with IL-13 interaction with IL-13Rα1 and IL-13Rα2. We found ∼10-fold higher circulating titer of captured IL-13 in subjects treated with IMA-026 compared with those administered IMA-638. To understand how this difference could be related to epitope, we asked whether either Ab affects IL-13 internalization through cell surface IL-13Rα2. Humans inducibly express cell surface IL-13Rα2 but lack the soluble form that regulates IL-13 responses in mice. Cells with high IL-13Rα2 expression rapidly and efficiently depleted extracellular IL-13, and this activity persisted in the presence of IMA-638 but not IMA-026. The potency and efficiency of this clearance pathway suggest that cell surface IL-13Rα2 acts as a scavenger for IL-13. These findings could have important implications for the design and characterization of IL-13 antagonists.
authors.affiliation: Department of Inflammation and Immunology, Pfizer Research, Cambridge, MA 02140, USA. marion.kasaian@pfizer.com
authors.forename: Marion T
authors.initials: MT
authors.lastname: Kasaian
authors.forename: Donald
authors.initials: D
authors.lastname: Raible
authors.forename: Kimberly
authors.initials: K
authors.lastname: Marquette
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Cook
authors.forename: Simon
authors.initials: S
authors.lastname: Zhou
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Tan
authors.forename: Lioudmila
authors.initials: L
authors.lastname: Tchistiakova
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D016503:Drug Delivery Systems; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D007518:Isoantibodies / Q000502:physiology*; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D051116:Receptors, Scavenger / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
chemical_list: D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D007518:Isoantibodies; D051116:Receptors, Scavenger