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IL-2 and IL-15 Blockade by BNZ-1, an Inhibitor of Selective γ-chain Cytokines, Decreases Leukemic T-cell Viability

T Tiffany Wang, Jun Yang, Yong Zhang, Meili Zhang, Sigrid Dubois, Kevin C Conlon, Yutaka Tagaya, Cait E Hamele, Shubha Dighe, Thomas L Olson, David J Feith, Nazli Azimi, Thomas A Waldmann, Thomas P Loughran Jr

Leukemia. 2019 May;33(5):1243-1255.

PMID: 30353031

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.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
IAR42413353 IL-15 from mouse IL-15 from mouse Price
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