A novel therapeutic strategy targeting multiple members of the γc-family cytokines; principles, relevance and potentially broad clinical applications.

Abstract

Cytokines play diverse roles in normal and abnormal immunity. Dysregulated production of cytokines underlies a variety of disorders in humans by causing improper immune responses. Intervention to such abnormal cytokine action has been utilized in the clinical field as "anti-cytokine therapy" and proven effective as treatments. However the current anti-cytokine approaches lack effective and safe options for treating human diseases involving more than two cytokines as the pathogenic reason. This is an issue as the list of multi-cytokine diseases is expanding. To address this, a novel technology was developed by generating a novel class of multi-cytokine inhibitors (MCI). In short, cytokine-mimetic peptides were rationally designed each of which contains a motif shared only by the cytokines of the target and tested using specific biological assay. Peptides showing desired antagonistic activity were screened further for target specificity. The lead MCI, BNZ 132-1, specifically inhibits IL-2, -9 and -15 while it does not affect other γc-cytokines (IL-4, -7. and -21) or non-γc cytokines. This design ensures safety of the peptide upon clinical use by limiting off-target effects to the minimum, unlike small-molecule Jak kinase inhibitors which suppress a diverse array of cytokines and cause multiple adverse effects. Currently, we are conducting clinical trials involving BNZ 132-1 and saw expected transient decrease of select subsets of lymphocytes with minimum toxicity. BNZ 132-1 may provide a novel opportunity for treating many diseases such as myelopathy caused by human T-cell leukemia virus-1 (HTLV-1), non-viral human T-cell malignancies, autoimmunity (Alopecia areata, rheumatoid arthritis), graft-versus-host disease (GvH) upon transplant and cytokine release syndromes post microbial infections.