Clinical trial of a humanized anti-IL-2/IL-15 receptor β chain in HAM/TSP.

Objective: Human T cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease. Chronic activation of CD8 T cells, as evidenced by increased spontaneous lymphoproliferation and HTLV-1-specific cytotoxic T cells, has been demonstrated in HAM/TSP patients. Since IL-2 and IL-15 stimulate memory CD8 T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/TSP. In this phase I trial, we evaluated the safety, pharmacokinetics, and ability of Hu-Mikβ1, a humanized monoclonal antibody directed toward the IL-2/IL-15 receptor β-chain (IL-2/IL-15Rβ: CD122), to saturate CD122 and regulate abnormal immune responses in patients with HAM/TSP by inhibition of IL-15 action.

Methods: Hu-Mikβ1 was administered intravenously at doses of 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg in a total of nine HAM/TSP patients. Five doses of Hu-Mikβ1 were administered at 3-week intervals. The clinical response was evaluated using standardized scales. Viral and immunologic outcome measures were examined including HTLV-1 proviral load, T cell phenotypic analysis and spontaneous lymphoproliferation in HAM/TSP patients.

Results: There was no significant toxicity associated with Hu-Mikβ1 administration in HAM/TSP patients. Saturation of CD122 by Hu-Mikβ1 was achieved in five out of nine HAM/TSP patients. Administration of Hu-Mikβ1 was associated with inhibition of aberrant CD8 T cell function including spontaneous lymphoproliferation and degranulation and IFN-γ expression, especially in HAM/TSP patients that achieved CD122 saturation.

Interpretation: The treatment with Hu-Mikβ1 had a number of immunological effects on HAM/TSP patients although no clinical efficacy was observed. We also did not see any dose-related toxicity.