MRT-6160, a VAV1-directed molecular glue degrader (MGD), inhibits disease progression, pro-inflammatory cytokines and autoantibody production in a model of rheumatoid arthritis
Initiation of MRT-6160 Phase 1 SAD/MAD study anticipated in mid-year 2024 with initial clinical data expected in Q1 2025
BOSTON, MA, USA I June 14, 2024 I Monte Rosa Therapeutics, Inc. (Nasdaq: GLUE), a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, today announced the company will present preclinical data at the European Alliance of Associations for Rheumatology (EULAR) 2024 Congress, being held June 12-15 in Vienna, Austria. The data demonstrated that in a collagen-induced arthritis (CIA) murine model, oral dosing of MRT-6160 inhibited disease progression as compared to vehicle and anti-TNF, concomitant with reduced serum pro-inflammatory cytokines and anti-collagen II autoantibodies. In vitro, MRT-6160-mediated degradation of human VAV1 dose-dependently reduced T-cell receptor (TCR)- and B-cell receptor (BCR)-mediated activation, proliferation, and function in T- and B-cells, including cytokine and IgG secretion. VAV1 is a key signaling protein downstream of both the T-and B-cell receptors, and its degradation has potential to treat multiple T-cell, T/B-cell, and Th17-mediated autoimmune and inflammatory diseases.
“We believe these preclinical data support our hypothesis that targeting VAV1 has strong therapeutic potential for rheumatoid arthritis,” said Sharon Townson, Ph.D., Chief Scientific Officer of Monte Rosa Therapeutics. “The data being presented at EULAR showed that oral dosing of MRT-6160 led to decreased TCR- and BCR-mediated immune activation and reduced levels of clinically relevant pro-inflammatory cytokines and autoantibodies, as well as statistically significant reductions in clinical scores of disease activity, in the CIA murine model. Today’s data combined with data from other autoimmune disease models and our GLP toxicology data reinforce our belief in the therapeutic potential of VAV1 across multiple autoimmune and inflammatory diseases. We look forward to initiating our Phase 1 single ascending dose/multiple ascending dose (SAD/MAD) study of MRT-6160 this summer and sharing initial clinical data from that study in Q1 2025.”
The poster, entitled “MRT-6160, a VAV1-Directed Molecular Glue Degrader, Reduces Joint Inflammation and Autoantibody Production in a Collagen-Induced Arthritis Autoimmune Disease Model” (Poster Number 1200), will be presented today by Adam Cartwright, Ph.D., Senior Scientist II at Monte Rosa Therapeutics, at 14:45 CET / 8:45 a.m. ET.
Summary of findings:
- In a CIA murine model, MRT-6160-mediated mouse VAV1 (mVAV1) degradation was associated with significantly reduced clinical scores and inhibition of disease progression in mice, with observable impact on signs of arthritis compared to control and anti-TNF-treated mice.
- Analysis of murine serum samples from the CIA model showed that degradation of mVAV1 was associated with significantly reduced production of key pro-inflammatory cytokines, including IL-1β, IL-6, TNF, and IL-17A, and autoantibody production, including anti-collagen II IgG1.
- Primary human T- and B-cells treated with MRT-6160 in vitro resulted in dose-dependent attenuation of TCR- and BCR-mediated activation (CD69 expression) and effector function in T- and B-cells, including cytokine and IgG secretion.
About VAV1 and MRT-6160
VAV1, a Rho-family guanine nucleotide exchange factor, is a key signaling protein downstream of both the T-and B-cell receptors. VAV1 expression is restricted to blood and immune cells, including T and B cells. Preclinical studies have shown that targeted degradation of VAV1 protein via an MGD modulates both T- and B-cell receptor-mediated activity. This modulation is evident both in vitro and in vivo, demonstrated by a significant decrease in cytokine secretion, proteins vital for maintaining autoimmune diseases. Moreover, VAV1-directed MGDs have shown promising activity in preclinical models of autoimmune diseases and thus have the potential to provide therapeutic benefits in multiple systemic and neurological autoimmune indications, such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and dermatological disorders.
MRT-6160 is a potent, highly selective, and orally bioavailable degrader of VAV1, which has shown deep degradation of its target with no detectable effects on other proteins. Preclinical studies demonstrate MRT-6160 inhibits disease progression in in vivo autoimmunity models.
About Monte Rosa
Monte Rosa Therapeutics is a clinical-stage biotechnology company developing highly selective molecular glue degrader (MGD) medicines for patients living with serious diseases in the areas of oncology, autoimmune and inflammatory diseases, and more. MGDs are small molecule protein degraders that have the potential to treat many diseases that other modalities, including other degraders, cannot. Monte Rosa’s QuEEN™ (Quantitative and Engineered Elimination of Neosubstrates) discovery engine combines AI-guided chemistry, diverse chemical libraries, structural biology and proteomics to identify degradable protein targets and rationally design MGDs with unprecedented selectivity. The QuEEN discovery engine enables access to a wide-ranging and differentiated target space of well-validated biology across multiple therapeutic areas. Monte Rosa has developed the industry’s leading pipeline of MGDs, which spans oncology, autoimmune and inflammatory disease and beyond, and has a strategic collaboration with Roche to discover and develop MGDs against targets in cancer and neurological diseases previously considered impossible to drug. For more information, visit www.monterosatx.com.
SOURCE: Monte Rosa Therapeutics
Post Views: 1,371
MRT-6160, a VAV1-directed molecular glue degrader (MGD), inhibits disease progression, pro-inflammatory cytokines and autoantibody production in a model of rheumatoid arthritis
Initiation of MRT-6160 Phase 1 SAD/MAD study anticipated in mid-year 2024 with initial clinical data expected in Q1 2025
BOSTON, MA, USA I June 14, 2024 I Monte Rosa Therapeutics, Inc. (Nasdaq: GLUE), a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, today announced the company will present preclinical data at the European Alliance of Associations for Rheumatology (EULAR) 2024 Congress, being held June 12-15 in Vienna, Austria. The data demonstrated that in a collagen-induced arthritis (CIA) murine model, oral dosing of MRT-6160 inhibited disease progression as compared to vehicle and anti-TNF, concomitant with reduced serum pro-inflammatory cytokines and anti-collagen II autoantibodies. In vitro, MRT-6160-mediated degradation of human VAV1 dose-dependently reduced T-cell receptor (TCR)- and B-cell receptor (BCR)-mediated activation, proliferation, and function in T- and B-cells, including cytokine and IgG secretion. VAV1 is a key signaling protein downstream of both the T-and B-cell receptors, and its degradation has potential to treat multiple T-cell, T/B-cell, and Th17-mediated autoimmune and inflammatory diseases.
“We believe these preclinical data support our hypothesis that targeting VAV1 has strong therapeutic potential for rheumatoid arthritis,” said Sharon Townson, Ph.D., Chief Scientific Officer of Monte Rosa Therapeutics. “The data being presented at EULAR showed that oral dosing of MRT-6160 led to decreased TCR- and BCR-mediated immune activation and reduced levels of clinically relevant pro-inflammatory cytokines and autoantibodies, as well as statistically significant reductions in clinical scores of disease activity, in the CIA murine model. Today’s data combined with data from other autoimmune disease models and our GLP toxicology data reinforce our belief in the therapeutic potential of VAV1 across multiple autoimmune and inflammatory diseases. We look forward to initiating our Phase 1 single ascending dose/multiple ascending dose (SAD/MAD) study of MRT-6160 this summer and sharing initial clinical data from that study in Q1 2025.”
The poster, entitled “MRT-6160, a VAV1-Directed Molecular Glue Degrader, Reduces Joint Inflammation and Autoantibody Production in a Collagen-Induced Arthritis Autoimmune Disease Model” (Poster Number 1200), will be presented today by Adam Cartwright, Ph.D., Senior Scientist II at Monte Rosa Therapeutics, at 14:45 CET / 8:45 a.m. ET.
Summary of findings:
- In a CIA murine model, MRT-6160-mediated mouse VAV1 (mVAV1) degradation was associated with significantly reduced clinical scores and inhibition of disease progression in mice, with observable impact on signs of arthritis compared to control and anti-TNF-treated mice.
- Analysis of murine serum samples from the CIA model showed that degradation of mVAV1 was associated with significantly reduced production of key pro-inflammatory cytokines, including IL-1β, IL-6, TNF, and IL-17A, and autoantibody production, including anti-collagen II IgG1.
- Primary human T- and B-cells treated with MRT-6160 in vitro resulted in dose-dependent attenuation of TCR- and BCR-mediated activation (CD69 expression) and effector function in T- and B-cells, including cytokine and IgG secretion.
About VAV1 and MRT-6160
VAV1, a Rho-family guanine nucleotide exchange factor, is a key signaling protein downstream of both the T-and B-cell receptors. VAV1 expression is restricted to blood and immune cells, including T and B cells. Preclinical studies have shown that targeted degradation of VAV1 protein via an MGD modulates both T- and B-cell receptor-mediated activity. This modulation is evident both in vitro and in vivo, demonstrated by a significant decrease in cytokine secretion, proteins vital for maintaining autoimmune diseases. Moreover, VAV1-directed MGDs have shown promising activity in preclinical models of autoimmune diseases and thus have the potential to provide therapeutic benefits in multiple systemic and neurological autoimmune indications, such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and dermatological disorders.
MRT-6160 is a potent, highly selective, and orally bioavailable degrader of VAV1, which has shown deep degradation of its target with no detectable effects on other proteins. Preclinical studies demonstrate MRT-6160 inhibits disease progression in in vivo autoimmunity models.
About Monte Rosa
Monte Rosa Therapeutics is a clinical-stage biotechnology company developing highly selective molecular glue degrader (MGD) medicines for patients living with serious diseases in the areas of oncology, autoimmune and inflammatory diseases, and more. MGDs are small molecule protein degraders that have the potential to treat many diseases that other modalities, including other degraders, cannot. Monte Rosa’s QuEEN™ (Quantitative and Engineered Elimination of Neosubstrates) discovery engine combines AI-guided chemistry, diverse chemical libraries, structural biology and proteomics to identify degradable protein targets and rationally design MGDs with unprecedented selectivity. The QuEEN discovery engine enables access to a wide-ranging and differentiated target space of well-validated biology across multiple therapeutic areas. Monte Rosa has developed the industry’s leading pipeline of MGDs, which spans oncology, autoimmune and inflammatory disease and beyond, and has a strategic collaboration with Roche to discover and develop MGDs against targets in cancer and neurological diseases previously considered impossible to drug. For more information, visit www.monterosatx.com.
SOURCE: Monte Rosa Therapeutics
Post Views: 1,371
