PC-9 Treatment of LGL leukemia by a novel cytokine inhibitor

Abstract

LGL-leukemia (LGL-L) is a rare type of lymphocyte malignancy originating from NK or CD8 T-cells. It accounts for 2–5% of chronic lymphoproliferative diseases and about 2000 patients are newly diagnosed every year in the US. Aggressive forms of LGL-L do not have an approved therapy and therefore represent unmet medical need. Signaling analysis/systems biology study and mouse models suggested that the CD8 type LGL-leukemic cells are dependent on 2 gamma-family cytokines, IL-2 and IL-15, in vivo, which promoted us to hypothesize that our novel multi-cytokine inhibitor, BNZ-1, would effectively treat LGL-leukemia. BNZ-1 is a 19mer peptide mimicking a preserved structure (D-helices) of all gamma-family cytokines (IL-2, -4, -7, -9-, 15 and -21). Since each gamma-family cytokine uses this region to interact with the shared gamma-receptor subunit (CD132) which transduces signal, BNZ-1 can compete with many gamma-family cytokines by blocking their binding to the gamma/CD132. Interestingly, it specifically blocks IL-2, IL-15 and IL-9 without inhibiting other cytokines, suggesting that the target specificities of BNZ-like peptides are dependent on their amino acid sequence. Because target cytokines of BNZ-1 are presumably causing LGL-leukemia, it is a suitable compound to treat LGL-L. Recent ex vivo studies in collaboration with the Loughran group at the University of Virginia (Dr. Tom Loughran discovered LGL-leukemia in 1985) showed that freshly isolated LGL-L cells from patients show proliferative response to IL-2 and IL-15, and their response was completely blocked by BNZ-1. BNZ-1 blocked multiple-branches of IL-2/IL-15 signaling in LGL-L cells and induced their quick apoptotic death. These results promoted us to test if we can treat LGL-L cases with BNZ-1. BNZ-1/PEG has been approved by the FDA as an IND and a phase I clinical trial targeting healthy individuals demonstrated that it reversibly blocks in vivo IL-2 and IL-15 action effectively (ie, profoundly reduces the number of NK and T-regs which are dependent on these 2 cytokine in vivo) with minimum adverse effects. For clinical use BNZ-1 peptide had been PEGylated (BNZ-1/PEG) and Pharmacokinetics data from Phase I study demonstrated that its biological half life is around 80 hours in humans, enabling a weekly dosing. Based on these observations, we are currently conducting a phase II clinical trial on LGL-L patients. For this trial, we are collaborating with BIONIZ therapeutics (Irvine, CA), and 4 major referral centers (Ohio State University Hospital, University of Virginia Hospital, City of Hope, and Moffitt Cancer Center) for LGL-L. Three LGL-L patients diagnosed at these Institutions were recruited to the program and treated with 0.5 mg/kg BNZ-1/PEG (a dose barely above the minimum effective dose) for 3 months (4 weekly intravenous injections of BNZ-1/PEG + 2 months of extended weekly injections, after patient's consent) with a promising lab finding that only LGL-L cells but not other blood cells showed robust apoptotic death in response to BNZ-1. Currently, 3 patients in cohort 2 are being treated with 1.0 mg/kg BNZ-1/PEG and some of them show improvements of clinical data as well. The adverse effects seem minimum to modest. We will next increase the treatment dose to 2.0 mg/kg (and to 4.0 mg/kg, if necessary) pending safety committee review, to continue our efforts to establish a new curative therapy for LGL-L.