Preclinical and phase I clinical trial of blockade of IL-15 using Mikβ1 monoclonal antibody in T cell large granular lymphocyte leukemia

John C. Morris, John Edward Janik, Jeffrey D. White, Thomas A. Fleisher, Margaret Brown, Mitsuru Tsudo, Carolyn K. Goldman, Bonita Bryant, Michael Petrus, Lois Top, Cathryn C. Lee, Wendy Gao, Thomas A. Waldmann

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56 Scopus citations

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 Mikβ1. Mikβ1 identifies CD122, the β-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. Mikβ1 treatment was not associated with significant toxicity or with the development of an immune response to the infused monoclonal antibody. At these doses of Mikβ1, >95% saturation of the IL-2/IL-15/3 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 Mikβ1 in groups of patients with human T cell lymphotropic virus I-associated myelopathy/tropical spastic paraparesis, rheumatoid arthritis, multiple sclerosis and refractory celiac disease.

Original languageEnglish (US)
Pages (from-to)401-406
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number2
DOIs
StatePublished - Jan 10 2006

Keywords

  • Cytokine
  • IL-2/IL-15β receptor (CD122)
  • Natural killer cells

ASJC Scopus subject areas

  • General

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    Morris, J. C., Janik, J. E., White, J. D., Fleisher, T. A., Brown, M., Tsudo, M., Goldman, C. K., Bryant, B., Petrus, M., Top, L., Lee, C. C., Gao, W., & Waldmann, T. A. (2006). Preclinical and phase I clinical trial of blockade of IL-15 using Mikβ1 monoclonal antibody in T cell large granular lymphocyte leukemia. Proceedings of the National Academy of Sciences of the United States of America, 103(2), 401-406. https://doi.org/10.1073/pnas.0509575103