Data from a CD117-ADC, an antibody-drug conjugate being developed by Magenta Therapeutics, were presented at the 61st annual meeting of the American Society of Hematology (ASH) being held December 7 – 10, 2019 in Orlando, Florida.
The investigational antibody-drug conjugates, CD117-ADC, targets CD117, a protein expressed on hematopoietic stem cells. The CD117-ADC, which includes an α-amanitin (an RNA polymerase inhibitor) payload conjugated to an CD117 antibody, is designed to remove the genetically mutated cells in the bone marrow that cause certain genetic diseases, such as sickle cell disease, enabling curative stem cell transplant or gene therapy.
Removing the cells that cause genetic disease is an important step in conditioning patients undergoing bone marrow transplant or stem cell gene therapy. However, while these approached may offer a curative therapy for blood and immune diseases with potential for many settings beyond current standard-of-care, these therapies are currently restricted to otherwise incurable malignant diseases. It is estimated that <25% of patients that could benefit from bone marrow transplant or stem cell gene therapy undergo transplantation.
The data from preclinical studies, presented by John Tisdale, MD, Director, Molecular and Clinical Hematology Section, National Institutes of Health (NIH), demonstrated the results of the first-ever transplant of gene-modified cells in non-human primates using a targeted, single-agent antibody-drug conjugate (ADC), without the use of chemotherapy or radiation.
The proof-of-concept study confirmed that a single dose of CD117-ADC fully depleted human hematopoietic stem cells in humanized mouse models. The data further confirmed that a single dose of CD117-ADC selectively depleted hematopoietic stem cells in non-human primates, while sparing immune cells, which are important for recovery following transplant.
CD117-ADC was engineered to have a fast half-life to clear the body quickly and enabled transplant of the gene-modified cells within days of dosing in non-human primates. The researchers observed that a single dose of CD117-ADC in non-human primates enabled successful transplant and engraftment of hematopoietic stem cells modified with a lentiviral vector encoding the β-globin gene, the gene that causes sickle cell disease and β-thalassemia. They confirmed that vector copy number was stable beyond three months, the longest time point in the study, suggesting that the gene-modified cells persisted in the body. This was comparable to historical data with multiple doses of busulfan* (Myleran, GlaxoSmithKline / Busulfex IV, Otsuka America Pharmaceutical) conditioning.
Overall, CD117-ADC was well tolerated in non-human primates with no evidence of the often severe side effects seen with busulfan conditioning, including veno-occlusive disease, weight loss, diarrhea, mucositis, vomiting, pulmonary fibrosis or seizures. Finally, the researchers did not observe any ADC-related blood chemistry changes outside normal range were observed.
These first proof-of-concept studies validate the use of CD117-ADC for targeted stem cell depletion prior to transplant and support its use as a new conditioning agent for gene therapy and stem cell transplant without toxic chemotherapy or radiation.
“Today’s conditioning regimens involve high doses of chemotherapy, often paired with radiation, to remove the disease-causing cells. As a result, patients undergoing gene therapy or stem cell transplant are all faced with a difficult choice: whether to endure severe toxicity and risk infertility and cancer for the chance for a cure. Magenta’s portfolio of targeted ADCs represents an extremely promising new option to prepare patients for gene therapy or transplant with no need for toxic chemotherapy or radiation,” Tisdale said.
“The results presented today show that a single dose of single agent CD117-ADC achieves the same level of depletion as four doses of busulfan chemotherapy to enable successful engraftment and persistence of stem cells modified with the β-globin gene, the gene that causes sickle cell disease and β-thalassemia when mutated. Importantly, the animals undergoing preparation with CD117-ADC showed none of the damaging toxicities associated with busulfan conditioning,” he added.
“Magenta is the only company with the people, platforms and a product engine committed to comprehensively transforming immune and blood system reset, which includes revolutionizing the toxic methods that are used to prepare patients for gene therapy and transplant today.” said Jason Gardner, D.Phil., Chief Executive Officer and President, Magenta Therapeutics.
“The gene therapy field has learned that higher levels of stem cell depletion, which meant higher doses of busulfan, were needed to ensure long-term engraftment of the gene-modified cells and persistence of gene therapy. Across all the modalities we have tested, we have seen that ADCs are most effective at achieving these high levels of stem cell depletion without chemotherapy to enable engraftment and long-term durability of the transplant,” Gardner concluded.
* Busulfane is a cell cycle non-specific alkylating antineoplastic agent initially approved 1959.
 Tisdale JF, Donahue RE, Uchida N, Pearse BR, McDonough S, Proctor JL, Krouse A, et al. A Single Dose of CD117 Antibody Drug Conjugate Enables Autologous Gene-Modified Hematopoietic Stem Cell Transplant (Gene Therapy) in Nonhuman Primates. 61st annual meeting of the American Society of Hematology. Abstratc # 610. Oral and Poster Abstract. Type: Oral. Session: 801. Gene Therapy and Transfer: Gene Therapies for Non-Malignant Disorders Hematology Disease Topics & Pathways: HSCs, antibodies, Biological, sickle cell disease, Diseases, Animal models, Therapies, thalassemia, Biological Processes, Genetic Disorders, Technology and Procedures, Hemoglobinopathies, Cell Lineage, gene therapy, Study Population, Clinically relevant, gene editing, hematopoiesis, transplantation, stem cells. [Abstract]
 Pearse B, Proctor J, McDonough S, Panwar R, Sarma G, Kien L, Dushime J, Adams H, Hyzy S, et al. A CD117-Amanitin Antibody Drug Conjugate (ADC) Effectively Depletes Human and Non-Human Primate Hematopoietic Stem and Progenitor Cells (HSPCs):Targeted Non-Genotoxic Conditioning for Bone Marrow Transplant. ASH December 10, 2019.[Presentation]
 Yao S, Hahn T, Zhang Y, et al. Unrelated donor allogeneic hematopoietic cell transplantation is underused as a curative therapy in eligible patients from the United States. Biol Blood Marrow Transplant. 2013;19(10):1459–1464. doi:10.1016/j.bbmt.2013.06.014
 Czechowicz A, Palchaudhuri R, Scheck A, et al. Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation. Nat Commun. 2019;10(1):617. Published 2019 Feb 6. doi:10.1038/s41467-018-08201-x