Volume 12 Supplement 1

17th International Conference on Human Retroviruses: HTLV and Related Viruses

Open Access

A multi-cytokine inhibitory peptide (BNZ 132-1) that is a potential therapeutic agent for HAMTSP and other necrotizing diseases.

  • Toshie Nata1,
  • Juan Carlos Zapata1,
  • Raya Massoud2,
  • Steve Jacobson2,
  • Nazli Azimi3 and
  • Yutaka Tagaya1Email author
Retrovirology201512(Suppl 1):O22

https://doi.org/10.1186/1742-4690-12-S1-O22

Published: 28 August 2015

We previously showed that the pathogenic mechanism of HAM-TSP involves the by-stander inflammatory damages of CNS cells by the hyper T-cell immunity caused by the HTLV-1. Thus we propose that suppressing this T-cell hyper-activation would be a key to prevent the progress of myelopathy in HAM-TSP. So far, three gc-family cytokines, IL-2, IL-15, and most likely IL-9 have been implicated in this process. Because these 3 cytokine share gc-subunit for signal transduction, they show functional redundancy. Because cellular responses to cytokines are sigmoid in shape with respect to cytokine doses, neutralizing one factor in a combination of 3 cytokines would not linearly lead to 33% inhibition even though the 3 factors were equally present in the mixture. This suggests that the use of a single monoclonal antibody (mAb) against one factor in a mixture of redundant cytokines often results in non-satisfactory effect, implying that a combinatorial blocking of all involved factors is needed to effectively treat clinical cases. A combined use of antibodies for each factor may solve the problem, but is infeasible in the clinic due to the costly nature of the Ab therapy. We therefore designed a peptide based on the conserved and divergent nature of the 6 gc-cytokines at their D-helix that is involved in their interaction with the gc-subunit. After computer simulated docking and high-throughput biological screening, we synthesized three peptides with different target specificities. The lead peptide (named BNZ 132-1) blocks IL-2, IL-9, and IL-15 in vitro. PEG-conjugation of this peptide enabled stability in vivo (T1/2 over 80 h in primates and in rodents) and efficiently blocked the in vivo propagation of an IL-15 dependent CD8 T cell leukemia in mice that we have generated in the past. In addition, BNZ 132-1 efficiently and specifically blocked the ex vivo activation and proliferation of CD8 T cells isolated freshly from HAM-TSP patients. We have already completed in vitro proof-of-concept, in vivo efficacy, toxicology/pharmacokinetics/pharmacodynamics studies and have obtained a patent on this compound. We will soon apply for the IND approval of this peptide for treating HAM-TSP. The structural nature, various unique biological characteristics and the drug potential of this peptide will be discussed.

Authors’ Affiliations

(1)
Cell Biology Lab, Institute of Human Virology, University of Maryland School of Medicine
(2)
Viral Immunology Section, National Institutes of Neuronal Diseases and Stroke
(3)
BIONIZ Inc.

Copyright

© Nata et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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