Intercepting activation of the NLRP3 inflammasome

RHAMM antagonist technology platform

Tissue injury results in the elaboration of endogenous danger signals that stimulate Toll-Like Receptors (TLRs). TLR signaling activates a signaling pathway that results in the formation of the NLRP3 inflammasome that initiates and amplifies inflammation. An activated NLRP3 inflammasome is a hallmark of severe inflammatory diseases for which there are no effective therapeutics.

Hyaluronan (hyaluronic acid, HA), a glycosaminoglycan component of the extracellular matrix, is an early and important endogenous danger signal and mediator of inflammation. In severe inflammatory diseases, HA is elevated and the receptor for hyaluronan-mediated motility (RHAMM) is expressed. RHAMM is an essential component of the signaling pathway that results in NLRP3 inflammasome activation. Consequently, RHAMM antagonists are a novel target for drug development.

Azome has developed AZM-152, a potent and specific RHAMM antagonist based on the Hyaluronan (HA) binding site on RHAMM. AZM-152 disrupts RHAMM function and prevents NLRP3 inflammasome activation.

Khan S, Shafiei MS, Longoria C, Schoggins J, Savani RC, Zaki H. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NFkB pathway. eLife, Dec 6;10:e68563, 2021. (PMID: 33758854)

Cui Z, Liao J, Cheong N, Longoria C, Cao G, DeLisser HM, Savani RC. The Receptor for Hyaluronan-Mediated Motility (CD168) promotes inflammation and fibrosis after acute lung injury. Matrix Biol. 78-79: 255-271, 2019 (PMID: 30098420)

Liao J, Kapadia VS, Brown LS, Cheong N, Longoria C, Mija D, Ramgopal M, McCurnin DC, Savani RC. The NLRP3 inflammasome is a key determinant in the development of Bronchopulmonary Dysplasia, Nature Communications, 6:8977, 2015. (PMID: 26611836)

Foley JP, Lam D, Jiang H, Liao J, Cheong N, McDevitt TM, Zaman A, Wright JR, Savani RC. TLR2, TGFβ, hyaluronan and RHAMM are required for Surfactant Protein A-stimulated macrophage chemotaxis, J Biol Chem., 287(44):37406-19, 2012. (PMID: 22948158)

Tolg C, Hamilton SR, Zalinska E, McCulloch L, Amin R, Akentieva N, Winnik F, Savani R, Bagli DJ, Luyt LG, Cowman MK, McCarthy JB, Turley EA. A RHAMM Mimetic Peptide Blocks Hyaluronan: RHAMM Interactions and Reduces Inflammation and Fibrogenesis of Excisional Skin Wounds, Am J Pathol., 181(4):1250-70, 2012. (PMID: 22889846)

Veiseh M, Breadner D, Ma J, Akentieva N, Savani RC, Harrison R, Mikilus D, Collis L, Gustafson S, Lee TY, Koropatnick J, Luyt LG, Bissell MJ, Turley EA. Imaging of homeostatic, neoplastic and injured tissues by HA-based probes. Biomacromolecules. 13(1): 12-22, 2012. (PMID: 22066590)

Garantziotis S, Li Z, Potts EN, Kimata K, Zhuo L, Morgan DL, Savani RC, Noble PW, Foster WM, Schwartz DA, Hollingsworth JW. Hyaluronan mediates ozone-induced airway hyperresponsiveness in mice. J Biol Chem. 284(17):11309-17, 2009. Erratum: J Biol Chem. 2016 Sep 9;291(37):19257-8. (PMID: 27613954; PMC: 5016665).

Zaman A, Cui A, Foley JP, Grimm PC, DeLisser DM, Savani RC. Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury. Am. J. Respir. Cell Mol. Biol.,33(5):447-454, 2005. (PMID: 16037485)

Savani RC, Hou G, Liu P, Wang C, Simons FE, Grimm PC, Stern R, Greenberg AH, DeLisser HM, Khalil N. A role for hyaluronan in bleomycin-induced pulmonary inflammation. Am J Respir Cell Mol Biol. 23:475-484. 2000. (Featured Cover Picture) (PMID: 11017912)

Lovvorn HN III, Cass DL, Yang E, Sylvester KG, Crombleholme TM, Adzick NS Savani RC. Hyaluronan receptor expression increases in fetal excisional skin wounds and correlates with fibroplasia. J Pediatr Surg. 33:1062-1070, 1998. (PMID: 9694095)

Savani RC, Wang C, Yang B, Zhang S, Kinsella M, Wight TN, Stern R, Nance DM, Turley EA. Migration of bovine aortic smooth muscle cells following wounding injury: the role of hyaluronan and RHAMM. J Clin Invest. 95:1158-1168, 1995. (PMID: 7533785)

Yang B, Yang BL, Savani RC, Turley EA. Identification of common hyaluronan (HA) binding motifs in the HA-binding proteins RHAMM, CD44 and link protein. The EMBO J. 13:286-296, 1993. (PMID: 7508860)

Published Research

Multiple in vitro and in vivo studies support the clinical development potential of AZM-152.

Demonstrated potency and RHAMM selectivity in NLRP3 inhibition.
Validated in proof-of-concept animal models including BPD, acute lung injury, pneumonia, and sepsis.