A stem cell transplant procedure involves three main steps:
(1) Mobilization and Collection – Stem cells from the patient’s or donor’s bone marrow are mobilized and then collected from the blood, in a process known as apheresis. When this does not work effectively, stem cells are surgically extracted from the bone marrow.
(2) Conditioning – The patient’s stem cells must be removed from the bone marrow to make room for the new transplanted stem cells. In cases where the patient is receiving cells from a donor, the patient’s immune cells must be removed so that they do not reject the incoming healthy stem cells.
(3) Transplantation and Engraftment – Stem cells are transplanted into the patient via infusion where they migrate and take residence in the bone marrow and grow into a healthy immune and blood system free of disease.
All transplants are categorized as either autologous or allogeneic, depending on the source of the new stem cells for the transplant:
- In an autologous transplant—used for conditions such as multiple myeloma, non-Hodgkin’s lymphoma and autoimmune diseases—the patient’s own stem cells are collected and used for the transplant. In the case of stem cell gene therapy and genome editing, once the cells are collected from the patient, these cells are then modified to either insert a functioning gene into, or correct a defective gene within, the collected stem cells before they are transplanted into the patient via infusion.
- In an allogeneic transplant—used for conditions such as acute leukemias and myelodysplastic syndromes—patients receive cells from a stem cell donor. The preferred source of stem cells for an allogeneic transplant is a donor who has a well-matched immune system. Finding a well-matched donor refers to analyzing the donor’s and recipient’s human leukocyte antigens (HLA) type to determine whether they are compatible, and therefore, more likely to lead to a successful transplant and better long-term outcomes. Full HLA matches are more commonly found in a patient’s siblings. For patients without a matched related donor, a matched unrelated donor may be identified through a bone marrow donor registry.
Where Magenta’s product candidates fit in:
Targeted Conditioning Programs
Stem cells need to be removed from a patient’s bone marrow before infusion of the new stem cells in the transplant. Current conditioning regimens present a tradeoff between superior long-term efficacy of high-intensity and toxic regimens (myeloablative conditioning) or improved safety and tolerability with lower efficacy (reduced intensity conditioning).
Magenta is developing a suite of novel antibody drug conjugates (ADCs) for conditioning, a step in the transplant process that currently relies on the use of systemic chemotherapy agents and radiation. We are seeking to replace these toxic, non-targeted conditioning agents with specific and targeted agents with better safety and efficacy profiles.
Magenta’s targeted conditioning programs are designed to selectively eliminate stem cells and/or immune cells from a patient prior to transplant or gene therapy, and to be far less toxic than the current radiation and chemotherapy-based treatments.
While ADCs are an established treatment for certain cancers, this is the first time that ADC technology is being developed for stem cell transplantation. These programs have the potential to spare patients from the collateral damage to all organs that results from systemic high dose/high intensity chemotherapy conditioning and expand the number of patients eligible for the curative power of blood and immune reset through stem cell transplant.
Our MGTA-117 program is our lead targeted conditioning product candidate. It is designed to selectively deplete stem cells from patients prior to transplant or HSC-based gene therapy to reduce the need for high-dose or high-intensity chemotherapeutic agents or, in the case of gene therapy applications, to potentially eliminate the need for chemotherapeutic agents altogether.
MGTA-117 targets CD117 receptor, which is highly expressed on the cell surface of HSCs and leukemia cells, making it an ideal target for conditioning across broad sets of diseases, including certain blood cancers, hemoglobinopathies (sickle cell disease and beta-thalassemia) and inherited metabolic disorders.
Clinical studies for MGTA-117:
- A Phase 1/2 clinical trial, is currently ongoing to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and potential anti-leukemic activity and to establish the minimum safe and biologically-effective dose of a single dose of MGTA-117 in participants with relapsed/refractory (R/R) CD117+ acute myeloid leukemia (AML) and participants with myelodysplastic syndrome with excessive blasts (MDS-EB).
CD45-ADC is a second targeted conditioning program in the preclinical stage that is advancing toward the clinic.
Stem Cell Mobilization and Collection
Magenta is developing MGTA-145 as a potentially new first-line standard of care for stem cell mobilization in a broad range of diseases, for both autologous and allogeneic transplants. MGTA-145, a CXCR2 agonist, works in combination with plerixafor, a CXCR4 antagonist, to harness a complementary physiological mechanism for stem cell mobilization.
The goal of MGTA-145 is to be the first-line, G-CSF-free mobilization approach for all patients and donors through rapid, reliable, predictable and well-tolerated mobilization and collection of high numbers of functional stem cells that can improve the patient experience, the physician experience and bring operational efficiency and cost savings to the overall system.
Clinical Studies for MGTA-145:
- Autologous Stem Cell Transplant of Multiple Myeloma Patients. A Phase 2 trial, in collaboration with Stanford University, of MGTA-145 was completed in combination with plerixafor, to mobilize and collect stem cells for transplant in multiple myeloma patients.
- Sickle Cell Disease – Stem Cell Mobilization and Collection in Patients; Cell Characterization; Gene Modification. A Phase 2 trial in collaboration with bluebird bio, Inc. to evaluate the safety and potential utility of MGTA-145, in combination with plerixafor, for the mobilization and collection of stem cells in patients with sickle cell disease is currently enrolling . The collected cells will be characterized in lab studies and Magenta plans to gene-modify the cells and evaluate their engraftment in established translational models.