Pipeline & Disease Focus

Pipeline & Disease Focus

Lead Indication: An Orphan Neurological Disease

HAM/TSP (HTLV-I Associated Myelopathy/Tropical Spastic Paraparesis) is a chronic neuro-inflammatory disease with clinical symptoms similar to multiple sclerosis (1, 2). The etiological agent of this disease has been known to be HTLV-I, the first human retrovirus discovered (1-4). HAM/TSP is an unmet medical need with no FDA-approved therapeutic.

HAM/TSP patients exhibit an elevated immune response in the periphery as well as in the CNS that is mediated, at least in part, by over expression of some cytokines such as IL-2, IL-9, and IL-15 (5-9). A rationale approach for therapeutic intervention, therefore, is to inhibit the functions of these cytokines. Two monoclonal antibodies (mAB) have been independently studied in clinical trials. A mAB against IL-2 receptor has shown promising efficacy in phase I/II clinical trials for treatment of HAM/TSP (10). A mAB that inhibits IL-15 receptor has demonstrated some efficacy in early clinical trials as well (unpublished data from NIH). However, the limitation to single mAB therapy is that it only blocks one cytokine pathway, leaving the other two corroborating cytokine pathways intact. A therapeutic regimen of cocktail mABs (combination of three independent mABs that inhibit IL-2, IL-15, and IL-9) may be scientifically rationale. However, it is not feasible as it will be exceedingly expensive and burdensome on patients.

As an alternative, we have developed a single peptide (BNZ132-1) that can selectively and simultaneously inhibit the functions of IL-2, IL-9, and IL-15, a novel strategy to substitute the cocktail mAB therapy. The benefit of this approach is its superior specificity as compared to general immune-suppressants and broader efficacy as compared to single mAB therapy.

Bioniz is conducting IND-enabling studies to start the phase I/II clinical trials of its lead asset, BZN132-1, for the treatment of HAM/TSP.

References:

1. Gessain A, Barin F, Vernant JC, Gout O, Maurs L, Calender A, de Thé G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. 1985 Lancet. 2:407-410.

2. Osame M, Usuku K, Izumo S, Ijichi N, Amitani H, Igata A, Matsumoto M, Tara M. HTLV-I associated myelopathy, a new clinical entity. 1986 Lancet. 1:1031-1032.

3. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415-7419.

4. Gallo RC. The discovery of the first human retrovirus: HTLV-1 and HTLV-2. 2005 Retrovirol 2: 17-25.

5. Tendler CL, Greenberg SJ, Blattner WA, et al. (1990) Transactivation of interleukin 2 and its receptor induces immune activation in human T-cell lymphotropic virus type I-associated myelopathy: pathogenic implications and a rationale for immunotherapy. 1990 Proc Natl Acad Sci U S A. 87:5218-5222.

6. Azimi, N., Jacobson, S., Leist, T., Waldmann, T.A., Involvement of IL-15 in the pathogenesis of human T lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis: implications for therapy with a monoclonal antibody directed to the IL-2/15R beta receptor. 1999 J. Immunol. 163:4064-4072.

7. Azimi, N., Brown, K., Bamford, R.N., Tagaya, Y., Siebenlist, U., Waldmann, T.A., Human T cell lymphotropic virus type I Tax protein trans-activates interleukin 15 gene transcription through an NF-kappaB site. 1998 Proc. Natl. Acad. Sci. USA 95:2452-2457.

8. Mariner JM, Lantz V, Waldmann TA, Azimi N. Human T cell lymphotropic virus type I Tax activates IL-15R alpha gene expression through an NF-kappa B site. 2001J Immunol. 166:2602-2609.

9. Jacobson S, Shida H, McFarlin DE, et al. Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease. 1990 Nature.348:245–248.

10. Lehky TJ, Levin MC, Kubota R, et al. Reduction in HTLV-I proviral load and spontaneous lymphoproliferation in HTLV-I-associated myelopathy/ tropical spastic paraparesis patients treated with humanized anti-Tac. 1998 Ann Neurol. 44:942-947.