B-101 Shooting many cytokines with a single Stone-a novel anti-cytokine technology with broad clinical application

Abstract

gc-cytokines (IL-2, -4, -7, -9, -15, -21) control major immune responses and lymphocyte development. Their aberrant production drives multiple human diseases including HTLV-1 associated myelopathy (HAM), T-cell malignancies, graft-versus-host (GvH) disease and autoimmunity (e.g., alopecia areata, Celiac disease, asthma). Importantly, these diseases are caused by 2 or more cytokines (multi-cytokine diseases) which cannot be effectively and safely treated by the current anti-cytokine approaches. To address this issue, we developed a novel class of multi-cytokine inhibitors (MCI) that are designed as cytokine-mimetic peptides each of which contains a short motif shared by only the targeted cytokines of the γc family. Our first MCI, BNZ 132-1, selectively inhibits IL-2, -9, -15 without affecting other γc- or non-γc-cytokines. BNZ 132-1 efficiently eradicated LGL leukemic cells without damaging normal cells in the IL-15 leukemic model we developed, in which a Jak inhibitor (Tofacitinib) showed only limited efficacy (Nata et al 2015 J Biol Chem). In humanized-mice infected with LCMV (a mouse model of cytokine release syndrome [CRS]), animals treated with BNZ 132-1 survived while all control animals died. BNZ 132-1 reversed the cytokine storm (IL-6, TNF-γ, IFN-γγ within 5 days, which is likely caused by the over-production of IL-2/IL-15). Similarly, GvH naturally occurring in humanized mice was effectively suppressed by the BNZ 132-1 treatment. These results suggest a potential application of BNZ 132-1 for GvH post transplantation and CRS post microbial infection, in addition to HAM and T-cell malignancies that we are targeting in our clinical trials. Thus, our new MCI technology fills in a major gap of anti-cytokine therapy.