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M3 Technology for First-in-Class Multi-Cytokine Inhibitors

Our proprietary technology platform, which we call Multi Modal Modulation (M3), has enabled the rational design of first-in-class peptide therapeutics, each of which can selectively inhibit multiple cytokines as a single agent by targeting the shared receptor in a cytokine family. For example, BNZ-1 peptide blocks the disease driving cytokines IL-2, IL-9, and IL-15, while allowing the other partners in the family to function normally and maintain heathy immune balance through their protective redundant functions.

BNZ peptide blocks the pockets in the common receptor

This approach is not feasible by either broadly inhibitory small molecules (e.g., JAK inhibitors) or large monoclonal antibodies (MABs). Most MABs are targeted against one cytokine and do not address the disease pathology adequately if more than one cytokine is implicated in the disease process. JAK inhibitors lack specificity and inhibit the JAK/STAT signaling pathway that is utilized by all the cytokines regardless of their involvement in the disease. As the result, this class of compounds are often associated with serious side effects. Furthermore, JAK inhibitors only block JAK/STAT pathway but two other signaling pathways, ERK and PI3K, remain functional and may continue to the drive the disease which may impact the clinical efficacy. BNZ peptides selectively block multiple disease driving cytokines while maintaining the healthy immune balance through the normal function of other family members.

BNZ peptides have a differentiated approach to multi-cytokine inhibition

Our M3 platform incorporates machine learning to unravel the unique structural and chemical nuances of common receptor usage within a cytokine family. This insight into how cytokine redundancy works at the molecular level enables our deep understanding of cytokine biology to create new classes of multi-cytokine peptide inhibitors with the potential to significantly advance the treatment of immune-mediated disorders, including auto-immune diseases and cancers.

Many diseases are driven by the collective dysregulation of multiple cytokines and are, therefore, inherently beyond the reach of current therapies that lack either the breadth or the specificity to address this more complex pathology. Our technology enables us to computationally merge the structural and chemical components required to modulate the signaling of specific cytokine combinations into a single molecule to create differentiated products that will improve outcomes for millions of patients who are suffering from immune-mediated diseases for which there are no treatments.


Co-Inhibition of IL-2, IL-9 and IL-15 By the Novel Immunomodulator, BNZ-1, Provides Clinical Efficacy in Patients with Refractory Cutaneous T Cell Lymphoma in a Phase 1/2 Clinical Trial. Querfeld, C., William, B., Sokol, L., Akilov, O., Poligone, B., Zain, j., Tagaya, Y., Azimi, N. ASH 2020 Presentation by Dr. Christiane Querfield of City of Hope. December 5th, 2020.

Results From a First-in-Human Study of BNZ-1, a Selective Multicytokine Inhibitor Targeting Members of the Common Gamma (γ c) Family of Cytokines. Frohna, P., Ratnayake, A., Doerr, N., Basheer, A., Al-Mawsawi, L.Q., Kim, W.J., Zapata, J.C., Wu, X., Waldmann, T.A., Azimi, N., Tagaya, Y. Journal of Clinical Pharmacology. February 2020

Identification of a γc Receptor Antagonist That Prevents Reprogramming of Human Tissue-resident Cytotoxic T Cells by IL15 and IL21. Ciszewski, C., Discepolo, V., Pacis, A., Doerr, N., Tastet, O., Mayassi, T., Maglio, M., Basheer, A., Al-Mawsawi, L.Q., Green, P., Auricchio, R., Troncone, R., Waldmann, T.A., Azimi, N., Tagaya, Y., Barreiro, L.B., Jabri, B., Gastroenterology. Oct 14th, 2019.

IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability. Wang, T.T., Yang, J., Zhang, Y., Meili, Z., Dubois, S., Conlon, K.C., Tagaya, Y., Hamele, C.E., Dighe, S., Olson, T.L., Feith, D.J., Azimi, N., Waldmann, T.A., and Loughran, T.P. Jr. Leukemia. May 2019.

Common γ-chain blocking peptide reduces in vitro immune activation markers in HTLV-1-associated myelopathy/tropical spastic paraparesis. Massoud, R., Enose-Akahata, Y., Tagaya, Y., Azimi, N., Basheer, A., Jacobson, S. PNAS. September 1st, 2015
Massoud et al, 2015.

A multi-cytokine inhibitory peptide (BNZ 132-1) that is a potential therapeutic agent for HAMTSP and other necrotizing diseases. Nata, T., Zapata, J.C., Massoud, R., Jacobson, S., Azimi, N., Tagaya, Y. Retrovirology. June, 2015.