CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Magenta Therapeutics, a biotechnology company developing therapeutics to improve and extend the use of curative bone marrow transplant for more patients, today announced the presentation of preclinical data from its hematopoietic stem cell (HSC) mobilization and expansion programs at the 59^th annual meeting of the American Society of Hematology (ASH) in Atlanta, Ga.

“Magenta is developing first-in-class, transformative drugs to extend the curative potential of bone marrow transplant and cell therapies to more patients. We are building a platform based on decades of research and clinical experience to lead a new era of transplant medicine,” said Michael Cooke, Ph.D., chief scientific officer, Magenta Therapeutics. “These three presentations provide crucial new insights into stem cell mobilization, expansion and engraftment and advance our understanding of how to potentially optimize patient outcomes in bone marrow transplant.”

The Combination of GROβ and AMD3100 Leads to Rapid and Robust Mobilization of Hematopoietic Stem Cells in Nonhuman Primates (Abstract #1920)

Overview and results, presented by Patrick Falahee, Ph.D., Magenta Therapeutics, include:

• Transforming the standard of care for stem cell mobilization has the potential to improve both the process and outcomes of bone marrow transplant. Magenta is developing GROβ, a CXCR2 agonist used in combination with established mobilization agent plerixafor (also known as AMD3100), based on the physiological mechanisms that control cell migration. The current mobilization standard of care is G-CSF, which requires a minimum of 5 days of treatment and multiple outpatient visits, and is often associated with bone pain, nausea, headache and fatigue.
• In these studies in non-human primates, Magenta showed that a single administration of GROβ in combination with plerixafor induces robust mobilization of a transplantable dose of CD34+CD90+CD45RA- hematopoietic stem and progenitor cells within four hours of administration.
  • CD34+CD90+CD45RA- HSCs have been shown to be important for long-term engraftment and hematopoietic reconstitution, both of which influence patient outcomes in bone marrow transplant as well as gene therapy and genome editing approaches.
• These data suggest that GROβ with plerixafor may offer a more robust, safer and more practical alternative to G-CSF in autologous and allogeneic transplant, which could be particularly important for diseases such as sickle cell disease or multiple sclerosis, where G-CSF is contraindicated or associated with severe adverse events.
• Magenta plans to initiate IND-enabling studies of GROβ with plerixafor.

Phenotype Does Not Always Equal Function: HDAC Inhibitors and UM171, but not SR1, Lead to Rapid Upregulation of CD90 on Non-Engrafting CD34+CD90-Negative Human Cells (Abstract #659)

Overview and results, presented by Kevin Goncalves, Ph.D., Magenta Therapeutics, include:

• Generating a higher dose of hematopoietic stem cells (HSCs) for bone marrow transplant can have a significant impact on engraftment and hematopoietic reconstitution, both of which influence patient outcomes in bone marrow transplant as well as gene therapy/genome editing approaches. Several approaches exist for expanding HSCs ex vivo to generate higher cell doses.
• CD34+CD90+CD45RA- HSCs have been shown to be important for long-term engraftment and hematopoietic reconstitution -- recent studies in non-human primates have shown that all the short-term and long-term engraftment activity is exclusively found in this cell population. In the current study, Magenta scientists extended this finding to human HSCs and show that for both fresh and ex vivo expanded cells, only the CD90 positive subset is able to engraft NSG mice.
• Magenta scientists used this knowledge of HSC phenotype to compare several small molecule approaches reported to expand human HSCs, including the aryl hydrocarbon reception (AHR) antagonist SR1; histone deacetylase (HDAC) inhibitors; and UM171, a small molecule with unknown mechanism.
• The data showed that while all methods increased the number of CD34+CD90+CD45RA- cells in vitro, AHR antagonists led to the largest increase in engrafting human HSCs in animals. Notably, cells cultured with HDAC inhibitors failed to engraft despite containing high numbers of CD34+CD90+CD45- cells.
• Cell sorting experiments revealed that culture with HDAC inhibitors and UM171 leads to rapid upregulation of HSC markers (CD90 and loss of CD45RA) on CD34+CD90-negative progenitor cells. These results suggest that most of the CD34+CD90+CD45RA- cells generated with HDAC inhibitors and UM171 arise from upregulation of CD90 rather than expansion of true CD34+CD90+CD45RA- cells and may explain the discrepancy between the in vitro phenotype and in vivo engraftment results observed with these compounds.
• These results suggest that AHR inhibition is an optimal method for ex vivo expansion of human hematopoietic stem cells. Magenta is advancing this expanded stem cell product (MGTA-456) in clinical trials (see abstract #662).

AHR Antagonists Expand Adult Hematopoietic Stem Cells from Mobilized Peripheral Blood and Bone Marrow and Increase the Dose of CRISPR/Cas9 Gene-Edited NSG-Repopulating Cells (Abstract #3341)

Overview and results, presented by Megan Hoban, Ph.D., Magenta Therapeutics, include:

• Gene-modified hematopoietic stem cell transplant (genome editing/gene therapy) is a promising treatment approach for a number of inherited diseases but is limited by:
  • The inability to generate a sufficient dose of gene-modified HSCs
  • The need for myeloablative conditioning to achieve engraftment
• Based on extensive medicinal chemistry work, Magenta Therapeutics developed a proprietary AHR antagonist as a potential approach to generate higher gene-modified cell doses by expanding the numbers of gene-modified HSCs ex vivo.
• In this study, human HSCs from both mobilized peripheral blood and bone marrow were edited with CRISPR/Cas9 technology, expanded with the AHR antagonist and then transplanted into NSG mice.
• Expanded cells showed up to a 34-fold increase in the number of CD34+CD90+ HSCs during in vitro culture, and when these expanded cells were transplanted into NSG mice, they resulted in twice the number of human cells engrafting in vivo compared to controls.
• Importantly, the high levels of editing of the expanded cells obtained during the in vitro culture (~80%) were maintained in vivo, demonstrating that the expanded-edited HSCs can retain engraftment activity.
• Preclinical studies are ongoing to examine the ability of the AHR antagonist to expand HSCs transduced with lentiviral vectors.

About Bone Marrow Transplant

Healthy bone marrow stem cells and the blood cells they create are crucial for survival, but certain diseases can affect the bone marrow, interfering with its ability to function properly. A bone marrow transplant is a process to replace unhealthy bone marrow with healthy bone marrow stem cells. Bone marrow transplant can save the lives of patients with blood cancers and genetic diseases and is a potential cure for patients with severe refractory autoimmune diseases. However, the high risks, toxic side effects and complexity of the procedure currently prevent many patients from being able to benefit.

About Magenta Therapeutics

Magenta Therapeutics is a biotechnology company developing therapeutics to revolutionize bone marrow transplant for patients with autoimmune diseases, blood cancers and genetic diseases. By creating a platform focused on critical areas of transplant medicine, Magenta Therapeutics is pioneering an integrated approach to extend the curative power of bone marrow transplant to more patients. Founded by internationally recognized leaders in bone marrow transplant medicine, Magenta Therapeutics was launched in 2016 by Third Rock Ventures and Atlas Venture and is headquartered in Cambridge, Mass. For more information, please visit www.magentatx.com.

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