IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability

• Published in: Leukemia Vol. 33; no. 5; pp. 1243 - 1255
• Main Authors: Wang, T. Tiffany, Yang, Jun, Zhang, Yong, Zhang, Meili, Dubois, Sigrid, Conlon, Kevin C., Tagaya, Yutaka, Hamele, Cait E., Dighe, Shubha, Olson, Thomas L., Feith, David J., Azimi, Nazli, Waldmann, Thomas A., Loughran, Thomas P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2019; Nature Publishing Group
• Subjects: 13/106; 59/5; 631/250/127/98; 631/67/1059/602; 64/110; 692/308/2778; 692/699/249/1623; 82/80; 96/2; 96/21; 96/95; Animals; Annexin A5 - metabolism; Apoptosis; Apoptosis - drug effects; Benzodiazepines - pharmacology; Cancer Research; CD4 antigen; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell viability; Chains; Critical Care Medicine; Cytokines; Cytokines - metabolism; Cytotoxicity; Dependence; Disease Models, Animal; Hematology; Humans; Intensive; Interleukin 15; Interleukin 2; Interleukin 9; Interleukin-15 - antagonists & inhibitors; Interleukin-2 - antagonists & inhibitors; Internal Medicine; Janus Kinases - metabolism; Leukemia; Leukemia, T-Cell - metabolism; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Mice; Oncology; Phosphorylation; Receptors; Signal Transduction - drug effects; Signaling; STAT Transcription Factors - metabolism; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-018-0290-y

Interleukin-15 (IL-15) and IL-2 drive T-cell malignancies including T-cell large granular lymphocyte leukemia (T-LGLL) and HTLV-1 driven adult T-cell leukemia (ATL). Both cytokines share common γ-chain receptors and downstream signaling pathways. T-LGLL is characterized by clonal expansion of cytotoxic T cells and is associated with abnormal JAK/STAT signaling. ATL is an aggressive CD4+ T-cell neoplasm associated with HTLV-1. T-LGLL and ATL share dependence on IL-2 and IL-15 for survival and both diseases lack effective therapies. BNZ-1 is a pegylated peptide designed to specifically bind the γc receptor to selectively block IL-2, IL-15, and IL-9 signaling. We hypothesized that treatment with BNZ-1 would reduce cytokine-mediated proliferation and viability. Our results demonstrated that in vitro treatment of a T-LGLL cell line and ex vivo treatment of T-LGLL patient cells with BNZ-1 inhibited cytokine-mediated viability. Furthermore, BNZ-1 blocked downstream signaling and increased apoptosis. These results were mirrored in an ATL cell line and in ex vivo ATL patient cells. Lastly, BNZ-1 drastically reduced leukemic burden in an IL-15-driven human ATL mouse xenograft model. Thus, BNZ-1 shows great promise as a novel therapy for T-LGLL, ATL, and other IL-2 or IL-15 driven hematopoietic malignancies.