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Molecular targets for therapy

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

Abstract

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.

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Acknowledgements

LGL leukemia patient samples and clinical information were obtained from the LGL Leukemia Registry at the University of Virginia with the assistance of Holly Davis, Bryna Shemo and Andrea Hines. Alexander Wendling and Matthew Schmachtenberg provided excellent technical support while processing patient samples. We thank Yadeliz Adlin Serrano Matos (University of Puerto Rico, Rio Piedras Campus) for assistance with Supplementary Figure 3. We thank Alexander Wendling in the UVA Flow Cytometry Core for assistance with apoptosis assays. NKL cells, a leukemic LGL NK-cell line, were kindly provided by Dr. Howard Young at the National Cancer Institute. We thank Taconic Inc. (Petersburg, NY) for providing the human IL-15 transgenic mice. This research was funded by the National Cancer Institute of the National Institutes of Health under award number R01CA098472, R01CA178393, and P30CA044579 (T.P.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional funding was provided to T.P.L. by the Bess Family Charitable Fund, the LGL Leukemia Foundation, and a generous anonymous donor. This research was also supported in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research (T.A.W).

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Conflict of interest

Nazli Azimi and Yutaka Tagaya are employed by BIONIZ Therapeutics, the producer of BNZ-1. Thomas Loughran, Jr. and Thomas Waldmann are on the scientific advisory board of BIONIZ Therapeutics. The remaining authors declare that they have no conflict of interest.

Correspondence to Thomas A. Waldmann or Thomas P. Loughran Jr..

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