Technology

Releviate Therapeutics is addressing unmet needs in chronic pain. We offer first-in-class inhibitors whose development is rooted in actual pain pathology and in directly inhibiting pain pathways. Releviate Therapeutics directly targets pain.

There are two major products: RLVT-9-01 (anti-MMP-9 antibody) and RLVT-14-02 (anti-MMP-14 antibody).

Small-molecule-based synthetic inhibitors are non-selective and exhibited multiple off-target effects. Due to the high similarity between matrix metalloproteinases (MMPs), all small-molecule-based inhibitors failed clinical trials. Releviate Therapeutics was able to address the specificity issue by using specially developed and selected human monoclonal antibodies against MMP-9 and MMP-14, respectively. READ MORE about our pre-clinical data.

MMPs consist of a large family of endopeptidases that require Zn2+ for their enzyme activity. MMPs play a critical role in inflammation through the cleavage of the extracellular matrix proteins, cytokines, and chemokine MMP inhibitors have been developed to target different kinds of inflammation-related diseases, such as arthritis, atherosclerosis, periodontitis, and cancer.

Although there are more than 20 members in the MMP family, the gelatinases MMP-9 and MMP-2 are two of the best-studied family members. After secretion, MMP-9 and MMP-2 are found in the extracellular matrix, cerebrospinal fluid, and serum. MMP-9 and MMP-2 are activated by other proteases. For instance, MMP-9 is activated by plasminogen/plasmin and MMP-3, and MMP-2 is activated by MMP-14. The activity of MMP-2 and MMP-9 can be easily detected using the gelatin-substrate zymography assay. While MMP-2 is constitutively expressed in many tissues, MMP-9 is highly inducible. The activity of MMPs is regulated by endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMP). For example, the activity of MMP-9 and MMP-2 is inhibited by TIMP-1 and TIMP-2, respectively. LEARN MORE about the Mechanism of Action of RLVT-9-01 (anti-MMP-9 antibody) and RLVT-14-02 (anti-MMP-14 antibody).

The timeline below highlights our technology development and related publications. Releviate technology is the product of 20 years of extensive collaborative work between basic, translational, and clinical scientists from Duke University School of Medicine (Department of Anesthesiology), UC San Diego School of Medicine (Department of Anesthesiology), UC Riverside (Department of Bioengineering), and Sanford Burnham Research Institute (Biochemistry of MMPs).

2000

Upregulation and interaction of TNFalpha and gelatinases A and B in painful peripheral nerve injury

VI Shubayev, RR Myers
Brain research 855 (1) 83-89

2002

Endoneurial remodeling by TNFalph- and TNFalpha-releasing proteases. A spatial and temporal co-localization study in painful neuropathy

VI Shubayev, RR Myers
Journal of the Peripheral Nervous System 7 (1), 28-36

2004

Matrix metalloproteinase-9 promotes nerve growth factor-induced neurite elongation but not new sprout formation in vitro

VI Shubayev, RR Myers
Journal of neuroscience research 77 (2), 229-239

2006

The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets

RR Myers, WM Campana, VI Shubayev
Drug discovery today 11 (1-2), 8-20

2006

TNFalpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve

VI Shubayev, M Angert, J Dolkas, WM Campana, K Palenscar, RR Myers
Molecular and Cellular Neuroscience 31 (3), 407-415

2007

Cytokine regulation of MMP-9 in peripheral glia: Implications for pathological processes and pain in injured nerve

S Chattopadhyay, RR Myers, J Janes, V Shubayev
Brain, behavior, and immunity 21 (5), 561-568

2008

MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage

H Kobayashi, S Chattopadhyay, K Kato, J Dolkas, S Kikuchi, RR Myers, …
Molecular and Cellular Neuroscience 39 (4), 619-627

2009

MMP-9 controls Schwann cell proliferation and phenotypic remodeling via IGF-1 and ErbB receptor-mediated activation of MEK/ERK pathway

S Chattopadhyay, VI Shubayev
Glia 57 (12), 1316-1325

2010

Matrix Metalloproteinase Inhibition Enhances the Rate of Nerve Regeneration In Vivo by Promoting De-Differentiation and Mitosis of Supporting Schwann Cells

H Liu, Y Kim, S Chattopadhyay, I Shubayev, J Dolkas, VI Shubayev
Journal of Neuropathology & Experimental Neurology 69 (4), 386-395

2012

Immunodominant fragments of myelin basic protein initiate T cell-dependent pain

H Liu, SA Shiryaev, AV Chernov, Y Kim, I Shubayev, AG Remacle, …
Journal of neuroinflammation 9 (1), 119

2012

The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration

Y Kim, AG Remacle, AV Chernov, H Liu, I Shubayev, C Lai, J Dolkas, …
PloS one 7 (3), e33664

2015

Matrix metalloproteinase-14 both sheds cell surface neuronal glial antigen 2 (NG2) proteoglycan on macrophages and governs the response to peripheral nerve injury

T Nishihara, AG Remacle, M Angert, I Shubayev, SA Shiryaev, H Liu, …
Journal of Biological Chemistry 290 (6), 3693-3707

2015

Matrix Metalloproteinase (MMP) Proteolysis of the Extracellular Loop of Voltage-gated Sodium Channels and Potential Alterations in Pain Signaling

AG Remacle, S Kumar, K Motamedchaboki, P Cieplak, S Hullugundi, …

Journal of Biological Chemistry 290 (38), 22939-22944

2017

Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain

S Hong, AG Remacle, SA Shiraev, W Choi, SK Hullugundi, J Dolkas
Brain, behavior, and immunity 60, 282-292

2018

Acute- and late-phase matrix metalloproteinase (MMP)-9 activity is comparable in female and male rats after peripheral nerve injury

AG Remacle, SK Hullugundi, J Dolkas, M Angert, AV Chernov, …
Journal of neuroinflammation 15 (1), 89е