Humanized antibody directed to the IL-2 receptor β-chain prolongs primate cardiac allograft survival

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-2Rα, IL-2Rβ, and IL-2Rγ. Murine Mikβ1, a mAb that blocks IL-2 binding to IL-2Rβ, was developed as an immunosuppressive agent. There was modest prolongation of cynomolgus cardiac allograft survival in animals treated with murine Mikβ1 (mean survival 11.8 ± 1.6 days compared with 8.2 ± 0.4 days in untreated animals; p = 0.06). However, murine Mikβ1 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 Mikβ1, which is a largely human IgG1k Ab, except that murine hypervariable regions are retained, was developed. In vivo plasma survival of humanized Mikβ1 was threefold longer than simultaneously administered murine Mikβ1 (terminal t( 1/2 ), 104 ± 10 h vs 37 ± 2 h). Furthermore, humanized Mikβ1 manifests Ab-dependent cellular cytotoxicity, an activity that is absent with the parental murine Mikβ1. Graft survival was significantly prolonged by humanized Mikβ1 treatment with survivals of 22, 22, 24, 27, 44, and >300 days (p vs control <0.01; p vs murine Mikβ1 <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- 2Rα subunits. There was no toxicity attributable to the use of Mikβ1 Abs. Thus, humanized Mikβ1 prolonged cardiac allograft survival in primates without toxicity and may be effective as an adjunct to standard immunosuppressive therapy.