Preclinical and phase I clinical trial of blockade of IL-15 using Mikbeta1 monoclonal antibody in T cell large granular lymphocyte leukemia.
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.
Morris
John C
JC
Metabolism Branch, Center for Cancer Research, and Office of Cancer Complementary and Alternative Medicine, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Janik
John E
JE
White
Jeffrey D
JD
Fleisher
Thomas A
TA
Brown
Margaret
M
Tsudo
Mitsuru
M
Goldman
Carolyn K
CK
Bryant
Bonita
B
Petrus
Michael
M
Top
Lois
L
Lee
Cathryn C
CC
Gao
Wendy
W
Waldmann
Thomas A
TA
D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D019898:Autocrine Communication / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007167:Immunotherapy; D019409:Interleukin-15 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology; D015458:Leukemia, T-Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008875:Middle Aged; D019899:Paracrine Communication / Q000187:drug effects; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D019409:Interleukin-15; D007376:Interleukin-2; D015375:Receptors, Interleukin-2