CD69

MRT-6160, a potent and highly selective VAV1-directed molecular glue degrader, represents a potential novel therapeutic approach for systemic and neurological autoimmune and inflammatory diseases Initial Phase 1 clinical results, including biomarker data to demonstrate pharmacodynamic effects, anticipated in Q1 2025 BOSTON, MA, USA I August 19, 2024 I Monte Rosa Therapeutics, Inc. (Nasdaq: GLUE), a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, today announced that the first participants have been dosed in a Phase 1, single ascending dose / multiple ascending dose (SAD/MAD), healthy volunteer study evaluating MRT-6160, a VAV1-directed MGD being developed for systemic and neurological autoimmune diseases. The Company expects to obtain initial data from the Phase 1 study in Q1 2025. “We are very pleased to initiate our Phase 1 clinical study of MRT-6160, a potent, highly selective, and orally bioavailable VAV1-directed MGD, which we believe is the first rationally designed MGD in clinical development for a non-oncology indication,” said Markus Warmuth, M.D., Chief Executive Officer of Monte Rosa Therapeutics. “Our MGD-based therapeutic approach is well suited to degrade proteins that have been challenging to address with conventional modalities, and we believe we have opportunities to apply our technology to well-characterized targets like VAV1 that were previously considered undruggable. By degrading VAV1, a key regulator of T- and B-cell receptor activity, MRT-6160 could offer a differentiated approach to treat multiple autoimmune and inflammatory diseases. The Phase 1 study of MRT-6160 is designed to provide early insights into safety, pharmacokinetics, VAV1 protein degradation, and key downstream pharmacodynamic markers including CD69, IL-2, IL-6, and IL-17, helping to further inform our clinical strategy. We look forward to sharing initial clinical data from the study in Q1 2025, and subsequently initiating anticipated proof-of-concept studies in ulcerative colitis, rheumatoid arthritis, and potentially other indications.” The development of MRT-6160 is supported by preclinical data in multiple models of autoimmune/inflammatory diseases and preclinical GLP toxicology data that suggest the potential for a differentiated therapeutic profile in T-cell, T/B-cell, and Th17-mediated systemic and neurologic autoimmune diseases. MRT-6160 has been shown to potently and selectively degrade VAV1 in vitro in human T and B cells and has demonstrated encouraging results in multiple preclinical studies of autoimmune disease, including in models of inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis. About MRT-6160 MRT-6160 is a potent, highly selective, and orally bioavailable investigational molecular glue degrader of VAV1, which in preclinical studies has shown deep degradation of its target with no detectable effects on other proteins. 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. Preclinical studies have demonstrated that MRT-6160 can inhibit disease progression in several 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

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 Poster presentation today at 14:45 CET / 8:45 a.m. ET June 14, 2024 -- 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. 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. 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. 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. The content above comes from the network. if any infringement, please contact us to modify.

A novel PET imaging technique can noninvasively detect active inflammation in the body before clinical symptoms arise, according to new research. Using a PET tracer that binds to proteins present on activated immune cells, the technique produces images of ongoing inflammation throughout the body, such as rheumatoid arthritis. This makes it easier for physicians to correctly diagnose and treat patients. A novel PET imaging technique can noninvasively detect active inflammation in the body before clinical symptoms arise, according to research published in the February issue of The Journal of Nuclear Medicine. Using a PET tracer that binds to proteins present on activated immune cells, the technique produces images of ongoing inflammation throughout the body, such as rheumatoid arthritis. This makes it easier for physicians to correctly diagnose and treat patients. Rheumatoid arthritis is the most common type of inflammatory arthritis and affects 18 million people worldwide. It is a complex autoimmune disease characterized by chronic inflammation. This inflammation can cause the destruction of cartilage and bone, eventually leading to limitations, disabilities, loss of function, decreased quality of life, and possibly shortened life expectancy. "A major interest of the rheumatology field is employing precision diagnostics to predict disease development in individuals with risk factors of rheumatoid arthritis," said Fredrik Wermeling, PhD, associate professor and group leader at the Department of Medicine, Division of Rheumatology, Center for Molecular Medicine (CMM) at the Karolinska Institutet, in Solna, Sweden. "The hope is to find ways to identify such individuals even before they get sick, with the goal of being able to treat them so they never develop the disease." CD69 is one of the earliest cell surface markers seen on cells experiencing inflammation and is present in the tissue of patients with active rheumatoid arthritis. As such, researchers evaluated the performance of the CD69-targeting PET agent, 68Ga-DOTA-ZCAM241, for early disease detection in a mouse model of inflammatory arthritis. In the study, mice were imaged with 68Ga-DOTA-ZCAM241 PET before and three, seven, and 12 days after induction of arthritis. Disease progression was monitored by clinical parameters, such as measuring body weight and scoring swelling in the paws. The uptake of 68Ga-DOTA-ZCAM241 in the paws was analyzed, and after the last PET scan, tissue biopsy samples analyzed for CD69 expression. A second group of mice received PET scans with a nonspecific control peptide. Increased uptake of the CD69-directed tracer 68Ga-DOTA-ZCAM241 was seen in the paws of mice with induced inflammatory arthritis three days after induction, which preceded the appearance of clinical symptoms five to seven days after induction. The uptake of 68Ga-DOTA-ZCAM241 also correlated with the clinical score and disease severity. The nonspecific control peptide demonstrated only low binding. "68Ga-DOTA-ZCAM241 is a potential candidate for PET imaging of activated immune cells during rheumatoid arthritis onset," stated Olof Eriksson, PhD, associate professor and group leader of Translational PET Imaging at the Department of Medicinal Chemistry at Uppsala University, in Uppsala, Sweden. "We know that physicians are asking for better methods to image inflammation, for example in rheumatoid arthritis, and we hope this technology will be broadly used in many diseases that involve activated immune cells and inflammation.