Rheos and Cryostem Collaborate to Evaluate MALT1‑Targeted Therapeutics for GvHD
October 27, 2021
Rheos Medicines and French nonprofit research organization Cryostem have entered a research to provide biological resources from hematopoietic stem cell transplantation patients in order to evaluate MALT1-targeted therapeutics, including Rheos’s lead product candidate, RHX-317, for Graft-versus-Host Disease, based on functional immunologic profiling of patients and identification of molecular signatures for MALT1 activity.
GVHD is a condition that can occur after an allogeneic stem cell transplant (the transfer of stem cells from a donor) in which the donated cells initiate an immune response and attack the transplant recipient’s organs. There are two major forms of GVHD: acute, which generally occurs within 100 days of transplant, and chronic, which generally occurs more than 100 days after transplant. Both forms are associated with significant morbidity and mortality and can affect multiple organ systems.
The collaboration supports a precision medicine approach to enable the treatment of GvHD, by defining the predominant metabolic pathways in the anabolic hub that drive key pathogenic pathways in GvHD patient subsets.
“Rheos’s therapeutic approach to target MALT1 for the treatment of GvHD is built on compelling findings that MALT1 activates cellular activity and signaling pathways that are dysregulated in GvHD. I look forward to continued progress with this MALT1 inhibitor that offers a promising new approach for patients with GvHD,” said Robert Zeiser, head of Tumor Immunology and Immune Modulation and professor at the University of Freiburg Medical Center in Germany.
MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a dual-function scaffolding molecule and paracaspase that is expressed preferentially in immune cells. In addition to its role in NF-κB mediated lymphocyte activation and proliferation, Rheos has shown that MALT1 activity is central to the anabolic shift that fuels pathogenic functions of immune cells. Inhibiting MALT1 attenuates the activity of multiple immune cell types simultaneously to dampen the inflammatory response in the activated immune system. Because of its role in cellular metabolism, the effects of MALT1 inhibition can be monitored by metabolite signatures, opening an opportunity to monitor disease and evaluate activity of therapeutics in patients and patient subsets.
The research program brings together the collaborators’ two domains of expertise to address the challenge of treating GvHD, a major cause of post-transplant morbidity and mortality in patients who undergo allogeneic HSCT. With its proprietary technology platform, Rheos brings insights from studies showing that MALT1 activity underpins the activation of multiple cell types and signaling pathways within a metabolic hub that is dysregulated in GvHD, as well as approaches to predict and stratify patient response to treatment. Cryostem operates through a national biobanking network bringing together transplant units and Biological Resources Centers to accelerate research in the area of complications of HSCT, housing the first and unique collection in Europe dedicated to HSCT complications. This collection of approximately 200,000 biological samples, taken from patients before and after transplant, support research projects that meet rigorous selection criteria by a world-renowned scientific committee.
“This research collaboration with the experts at CRYOSTEM will enable us to significantly build on our existing work in immune cells from healthy donors, and now study GvHD patient samples to evaluate the effect of inhibiting a key drug target on the activation state of multiple immune cells and the specific pathways that are dysregulated in GvHD,” said Dania Rabah, chief scientific officer of Rheos Medicines. “We believe the data generated under this collaboration can validate our precision medicine approach to identify novel patient subsets in autoimmune and inflammatory diseases, while also informing the clinical development plan for RHX-317, our novel MALT1 inhibitor drug candidate to treat GvHD.”
Under the terms of the research collaboration, Cryostem will provide Rheos with biological resources for post-transplant patients in three categories: those who developed acute GvHD, those who developed chronic GVHD, and those who did not develop GvHD. Rheos will evaluate therapeutic targets for GvHD by measuring the effectiveness of MALT1 inhibition against disease-relevant functions of immune cells, comparing results across the three different categories of patient samples to determine sensitivity of MALT1 inhibitor drug response and target validation in chronic GvHD. Rheos will also perform multi-omic analyses of patient samples to define signatures reflecting MALT1 therapeutic activity.
Upon successful completion of these initial studies, both parties may agree to expand the research to include larger GvHD patient cohorts and additional evaluation of patient subsets to predict therapeutic response for a potential precision medicine approach to GvHD.
Author: Rare Daily Staff
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