P-A2 Shooting many cytokines by a single stone

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Abstract

Introduction:

We are developing a new type of cytokine inhibitor that can block the action of more than 2 structurally related cytokines with selective target specificity. The in vitro proof-of-concept has been recently published (Nata et al JBC 2015, Massoud et al PNAS 2015). The PEGylated BNZ132-1 peptide strongly blocked IL-2 and/or IL-15 in vivo (in mice and macaques) but showed marginal toxicity. These two cytokines play crucial role for the activation of CD8 T cells in the development of HAM/TSP (HTLV-1 associated myelopathy). We will be commencing a clinical trial involving BNZ132-1 and HAM-TSP patients at the NIH this year. Functionally related cytokines often cause human diseases which cannot be treated efficiently by a single antibody therapy. Therapeutic combination of antibodies is too costly. Thus, our approach fills in the existing gap of the current therapy.

Discussion:

We are now testing the second peptide (BNZ132-2) that blocks IL-21 and -15. These 2 cytokines play causative roles in inflammatory bowel diseases and in the Celiac Disease. In particular, refractory Celiac disease (RCD) that shows little response to gluten-free diet is our target. RCD also shows high association of T-cell leukemia. Using IELs from Celiac Patients, we have identified unique combinatorial effects of IL-21 and IL-15 in signaling events. Celia Lymphocytes seem more dependent on the IL-15/21 combination. RNA-Seq also validated that some critical CTL genes are efficiently upregulated in response to the IL-21/15 combination. Most importantly, BNZ132-2 strongly blocked the IL-15/21 combination at many levels.

Conclusions:

RCD is extremely difficult to treat at the moment. Our peptide BNZ132-2 would provide a promising candidate for a novel treatment for RCD. Additionally, the combined use of BNZ132-1 and -2 blocks IL-2, -15, -9 and -21, majority of the T-cell activating cytokines without affecting the homeostasis of T-cells (maintained by IL-7) and would be a useful tool to control fatal cytokine storm upon viral infections.

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