Preclinical and phase I clinical trial of blockade of IL-15 using Mikbeta1 monoclonal antibody in T cell large granular lymphocyte leukemia

Abstract

Twelve patients with T cell large granular lymphocyte leukemia and associated hematocytopenia were treated in a phase I dose-escalation trial with the murine monoclonal antibody Mikbeta1. Mikbeta1 identifies CD122, the beta-subunit shared by the IL-2 and IL-15 receptors. At the doses administered in this study the antibody inhibited the actions of IL-15 on both natural killer and T cells and that of IL-2 when the intermediate-affinity IL-2 receptor was expressed. Mikbeta1 treatment was not associated with significant toxicity or with the development of an immune response to the infused monoclonal antibody. At these doses of Mikbeta1, >95% saturation of the IL-2/IL-15beta receptor (CD122) on the surfaces of the leukemic cells was achieved. Furthermore, in seven patients this led to the down-modulation of the receptor from the surfaces of the leukemic cells. Nevertheless, no patients manifested a reduction in peripheral leukemic cell count or an amelioration of their hematocytopenia. This latter observation may reflect the fact that the monoclonal T cell large granular lymphocyte leukemia leukemic cells of the patients did not produce IL-2 or IL-15 or require their actions for cell survival. In light of the lack of toxicity and lack of immunogenicity of the antibody observed in the present study and the role for IL-15 in the pathogenesis of autoimmune diseases, clinical trials should be performed using the humanized version of Mikbeta1 in groups of patients with human T cell lymphotropic virus I-associated myelopathy/tropical spastic paraparesis, rheumatoid arthritis, multiple sclerosis and refractory celiac disease.

Fig. 1.

Inhibition of IL-2- and IL-15-induced proliferation of 32Dβ cells by Mikβ1. (A) Effect of Mikβ1 on IL-2 (1 ng/ml)-induced proliferation. (B) Dose-response effects of the addition of the Mikβ1 antibody on IL-15 (20 ng/ml)-induced proliferation in 32Dβ cells. In these cells, which express only IL-2/IL-15Rβ and common γ-chain, both IL-2- and IL-15-induced proliferation were inhibited by the addition of Mikβ1.

Fig. 2.

Inhibition of IL-15- but not IL-2-induced proliferation of Kit-225 cells by Mikβ1. (A) Dose-response effects of the addition of 10 ng/ml Mikβ1 antibody or anti-Tac antibody on IL-2 (500 pg/ml)-induced proliferation of Kit-225 cells. (B) Effect of 10 ng/ml anti-Tac or Mikβ1 on IL-15 (3 ng/ml)-induced proliferation of Kit-225 cells that express IL-2Rα as well as IL-2/IL-15Rβ and the common γ-chain. In these Kit-225 cells, which express the high-affinity receptor for IL-2, Mikβ1 inhibited the proliferation induced by IL-15 but not that induced by IL-2.