title: Humanized antibody directed to the IL-2 receptor beta-chain prolongs primate cardiac allograft survival.
abstract: IL-2Rs are expressed by T cells activated in response to foreign histocompatibility Ags but not by normal cells. This difference in IL-2R expression is exploited by blockade of IL-2Rs to achieve immunosuppression. High affinity IL-2Rs involve three subunits, IL-2R alpha, IL-2R beta, and IL-2R gamma. Murine Mik beta 1, a mAb that blocks IL-2 binding to IL-2R beta, was developed as an immunosuppressive agent. There was modest prolongation of cynomolgus cardiac allograft survival in animals treated with murine Mik beta 1 (mean survival 11.8 +/- 1.6 days compared with 8.2 +/- 0.4 days in untreated animals; p = 0.06). However, murine Mik beta 1 is ineffective in recruiting primate effector cells and is neutralized by monkey Abs directed toward the infused Ab. To circumvent these limitations, a humanized form of Mik beta 1, which is a largely human IgG1k Ab, except that murine hypervariable regions are retained, was developed. In vivo plasma survival of humanized Mik beta 1 was threefold longer than simultaneously administered murine Mik beta 1 (terminal t1/2, 104 +/- 10 h vs 37 +/- 2 h). Furthermore, humanized Mik beta 1 manifests Ab-dependent cellular cytotoxicity, an activity that is absent with the parental murine Mik beta 1. Graft survival was significantly prolonged by humanized Mik beta 1 treatment with survivals of 22, 22, 24, 27, 44, and > 300 days (p vs control < 0.01; p vs murine Mik beta 1 < 0.01). Survival was not prolonged further (p > 0.3) by the addition of humanized anti-Tac, which blocks interaction of IL-2 with IL-2R alpha subunits. There was no toxicity attributable to the use of Mik beta 1 Abs. Thus, humanized Mik beta 1 prolonged cardiac allograft survival in primates without toxicity and may be effective as an adjunct to standard immunosuppressive therapy.
authors.affiliation: Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: S A
authors.initials: SA
authors.lastname: Tinubu
authors.forename: J
authors.initials: J
authors.lastname: Hakimi
authors.forename: J A
authors.initials: JA
authors.lastname: Kondas
authors.forename: P
authors.initials: P
authors.lastname: Bailon
authors.forename: P C
authors.initials: PC
authors.lastname: Familletti
authors.forename: C
authors.initials: C
authors.lastname: Spence
authors.forename: M D
authors.initials: MD
authors.lastname: Crittenden
authors.forename: G L
authors.initials: GL
authors.lastname: Parenteau
authors.forename: F M
authors.initials: FM
authors.lastname: Dirbas
authors.forename: M
authors.initials: M
authors.lastname: Tsudo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015375:Receptors, Interleukin-2