Data presented during the 46th annual (virtual) meeting of the European Society for Blood and Marrow Transplantation (EBMT), held August 29 to September 1, 2020, includes updates from Magenta Therapeutics’ CD45-ADC.
CD45-ADC is an investigational conditioning agent, demonstrating successful immune reset to halt disease progression in multiple models of sclerosis, systemic sclerosis, and inflammatory arthritis. The CD45-ADC also demonstrated the ability to achieve complete chimerism in allogeneic hematopoietic stem cell transplant (HSCT).
CD45-ADC is one investigational antibody-drug conjugates being developed by Cambridge-based Magenta Therapeutics.
“Our presentations at EBMT showcase Magenta’s integrated approach towards bringing the curative power of blood and immune system reset through stem cell transplant to more patients and across more therapeutic areas,” noted John Davis Jr., M.D., M.P.H., M.S., Head of Research & Development and Chief Medical Officer, Magenta Therapeutics, a clinical-stage biotechnology company.
“We are making significant strides towards expanding eligibility and improving patient outcomes given the far-reaching potential of our programs. We are relentlessly focused on progressing our programs forward and further into the clinic and are encouraged by our steady progress. We look forward to our continued momentum across our pipeline,” Davis added.
Targeting CD45
Magenta’s CD45-ADC program targets CD45, a type I transmembrane protein expressed on immune cells and all hemopoietic cells (except erythrocytes) that assists in cell activation, they are generally expressed on lymphomas, B-cell chronic lymphocytic leukemia, hairy cell leukemia, and acute nonlymphocytic leukemia. CD45-ADC is designed to remove the cells that cause autoimmune diseases to enable curative immune reset.
Resetting the immune system through autologous hematopoietic stem cell transplant (autoHSCT) is a highly effective treatment.
Autologous hematopoietic stem cell transplant is a multistep procedure that enables the destruction of the immune system and its reconstitution from hematopoietic stem cells. Originally developed for the treatment of hematological malignancies, the procedure has been adapted for the treatment of severe immune-mediated disorders and has demonstrated a durable response in halting evidence of inflammatory activity in selected patients with autoimmune diseases. [1] In some instances, AutoHSCT has induced long-term remission (up to 15 years) with 80% progression-free survival (OFS) in multiple sclerosis patients without the need for continued disease-modifying therapies (DMT).[2][3]
Likewise, the use of autoHSCT in scleroderma patients, a progressive inflammatory disease that is frequently fatal and has limited treatment options, has achieved superior outcomes in two randomized studies compared to the standard of care.
In a number of observational studies, multicenter randomized controlled clinical trials, and meta-analyses, high-dose chemotherapy with autoAHCT has been evaluated as a treatment for scleroderma, leading to impressive results which were achieved by a combination of the eradication of autoreactive immune effector cells and the re-establishment of self-tolerance, i.e., immune system reset.[4]
However, only a small fraction of eligible patients undergo autoHSCT, largely due to toxicity associated with current conditioning protocols.
Magenta has identified a lead antibody for this program and IND-enabling work on CD45-ADC is rapidly progressing in 2020.
During the annual meeting of the EBMT, investigators presented preclinical data demonstrating that a single dose of CD45-ADC removed disease-causing T-cells, enabling successful immune reset to halt disease progression and was well tolerated in three models of autoimmune disease including multiple sclerosis, systemic sclerosis, and inflammatory arthritis.[A]
In a separate poster, investigators also presented preclinical data demonstrating that a single dose of CD45-ADC is fully myeloablative and enables complete chimerism in a full mismatch allogeneic hematopoietic stem cell transplant (HSCT). This represents a substantial advance in establishing the potential of this targeted approach to conditioning to potently and safely enable immune reset in the allogeneic setting.[B]
Conditioning ADCs
Preclinical data from the Magenta’s ADC-conditioning programs also included MGTA-117 (previously known as CD117-ADC), a targeted, disease-modifying antibody-drug conjugate designed to selectively and rapidly remove disease-causing cells in the body and enable immune and blood system reset and long-term engraftment, without the need for aggressive chemotherapy or radiation.
MGTA-117 is an investigational ADC designed to condition stem cell transplant and gene therapy for patients with sickle cell disease or beta-thalassemia. The agent is Magenta’s most advanced conditioning program and is, according to a spokesperson of the company, on track with ongoing IND-enabling toxicology studies and progress in GMP manufacturing. Magenta expects to generate initial clinical data in 2021.
The study results are from a collaborative study with the National Institutes of Health (NIH) and demonstrate that a single dose of MGTA-117 molecule in non-human primates enables successful transplant and long-term engraftment of HSCs modified with a lentiviral vector encoding the β-globin gene, the gene that causes sickle cell disease and β-thalassemia.
MGTA-117 was well tolerated with none of the significant side effects that are seen with myeloablative dosing of busulfan chemotherapy.
Based on the available data, the investigators concluded that the targeted approach with MGTA-117 for safer conditioning could improve the risk-benefit profile for patients undergoing transplant and enable more patients to benefit from potentially curative therapies including gene therapy for multiple genetic diseases including sickle cell disease.[C]
Other developments
In May 2020, Magenta announced a collaboration with AVROBIO to evaluate the potential use of MGTA-117 for conditioning patients with one or more AVROBIO investigational lentiviral gene therapies.
The collaboration combines Magenta’s expertise in ADC-based conditioning with AVROBIO’s experience in lentiviral gene therapies. Under the collaboration, both companies will jointly evaluate MGTA-117 in conjunction with one or more of AVROBIO’s investigational gene therapies. Magenta will retain all commercial rights to MGTA-117. AVROBIO will retain all commercial rights to its gene therapies and will be responsible for the clinical trial costs related to the evaluation of MGTA-117 with AVROBIO’s gene therapies.
In June 2020, Magenta and Beam Therapeutics announced a non-exclusive collaboration to evaluate the potential use of MGTA-117. Under the terms of this agreement, Beam will be responsible for clinical trial costs related to the development of Beam’s base editors when combined with MGTA-117, while Magenta will continue to be responsible for all other development costs of MGTA-117. Magenta will also continue to develop MGTA-117 in other diseases, including blood cancers and genetic diseases. Each company will retain all commercial rights to their respective technologies.
Clinical trials
Stem Cell Therapy for Patients With Multiple Sclerosis Failing Alternate Approved Therapy- A Randomized Study – NCT00273364
Poster presentations
[A] Gillard GO, Proctor JL, Brooks M, Lamothe TL, Hyzy SL, McDonough S, Clark N, Palchaudhuri R., et al, A Novel Targeted Approach to Achieve Immune System Reset: CD45-Targeted Antibody-Drug Conjugates Ameliorate Disease in Preclinical Autoimmune Disease Models and Enable Auto HSCT (Abstract #O030) [Poster]
[B] Hyzy SL, Palchaudhuri R, Proctor JL, Pearse BR, Sarma GN, Gillard GO, Saha A, et al. A CD45-Targeted Antibody Drug Conjugate Enables Allogeneic Hematopoietic Stem Cell Transplantation as a Single Agent in Mice (Abstract #A174)[Poster]
[C] Boitano A, Tisdale J, Uchida N, Donahue R, Pearse B, McDonough S, Proctor J, Krouse A., et al. Single-Dose of Short Half-Life CD117 Antibody Drug Conjugate Enables Hematopoietic Stem Cell-Based Gene Therapy in Non-Human Primates (Abstract #O076) [Poster]
Reference
[1] Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi R. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat Rev Neurol. 2017;13(7):391-405. doi:10.1038/nrneurol.2017.81
[2] Bose G, Thebault SDX, Atkins HL, Freedman MS. Does Resetting the Immune System Fix Multiple Sclerosis? [published online ahead of print, 2019 Sep 12]. Can J Neurol Sci. 2019;1-10. doi:10.1017/cjn.2019.294
[3] Burt RK, Balabanov R, Burman J, et al. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. 2019;321(2):165-174. doi:10.1001/jama.2018.18743
[4] Sullivan KM, Majhail NS, Bredeson C, et al. Systemic Sclerosis as an Indication for Autologous Hematopoietic Cell Transplantation: Position Statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2018;24(10):1961-1964. doi:10.1016/j.bbmt.2018.06.025
Featured Image: © 2020 The European Society for Blood and Marrow Transplantation. Used with permission.
