Abstract OS3-3
 
SELECTIVE HSC-ABLATION USING ANTI-CD117 ANTIBODY DRUG CONJUGATE ENABLES SAFE AND EFFECTIVE MURINE AND HUMAN HEMATOPOIETIC STEM CELL TRANSPLANTATION Print
 
Agnieszka Czechowicz1,2,3, Rahul Palchaudhuri4,5,6, Amelia Scheck1,3,4, Yu Hu1, Jonathan Hoggatt4,5,7, Borja Saez4,5,8, Michael K. Mansour4,5,9, Florian Winau1, David T. Scadden4,5,7, Derrick J. Rossi1,4,7
1Boston Children’s Hospital, Program in Cellular and Molecular Medicine, Department of Medicine, Boston, MA, United States; 2Dana-Farber Cancer Institute and Boston Children’s Hospital, Division of Pediatric Hematology/Oncology, Boston, MA, United States; 3Stanford University, School of Medicine, Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford, CA, United States; 4Harvard University, Stem Cell and Regenerative Biology, Cambridge, MA, United States; 5Massachusetts General Hospital, Center for Regenerative Medicine, Boston, MA, United States; 6Magenta Therapeutics, Cambridge, MA, United States; 7Harvard Stem Cell Institute, Cambridge, MA, United States; 8Center For Applied Medical Research, Pamplona, Spain; 9Massachusetts General Hospital, Division of Infectious Diseases, Boston, MA, United States
 
Background: Hematopoietic stem cell transplantation (HSCT) can be curative for many blood and immune diseases. However, despite its widespread potential, today HSCT is primarily restricted to deadly malignant diseases with few other treatment options. In these situations, the potential benefit of HSCT outweighs the current risks. Although if made safer, HSCT could be applied in many more disease settings. The procedure today results in frequent morbidity/mortality mainly due to graft versus host disease and toxicity from irradiation/chemotherapy conditioning currently employed to enable donor HSC engraftment. Although many efforts have been undertaken to reduce toxic conditioning, most patients still suffer from side effects including organ damage, infertility, secondary malignancies, and cytopenias. Eliminating genotoxic conditioning would dramatically improve HSCT, which would be especially beneficial in gene therapy/gene editing settings where this is the major limitation to expanded use.
Methods: Over the last decade we have pioneered several novel antibody-based strategies to overcome the need for genotoxic conditioning. Specifically, we have previously shown that competition with host HSC limits donor HSC engraftment, and that antagonistic anti-CD117 antibodies depleting host HSC are an effective, safe alternative conditioning approach in immunodeficient mice (Czechowicz Science 2007). These antagonistic anti-CD117 antibodies were subsequently shown to be effective in conditioning wildtype mice, however additional strategies/agents were needed to enable donor engraftment which caused significant cytopenias (Xue Blood 2010, Chhabra Sci Trans Med 2016,). As an alternative, we developed anti-CD45 antibody-drug conjugates, however these induced a temporary lymphopenia which is not desirable in many settings (Palchaudhuri Nature Biotechnology 2016). To overcome these limitations, here we generated an exceptional anti-CD117 antibody-drug conjugate by linking non-antagonistic anti-CD117 antibodies to protein synthesis toxins.
Results: These anti-CD117-saporin antibody-drug conjugates led to >99.9% depletion of host HSCs and subsequently enabled rapid >99.9±0.1% engraftment of donor murine whole bone marrow cells and >69.0±12.8% engraftment of donor murine purified HSCs in a cell dose dependent manner. Importantly and uniquely, these non-genotoxic agents did not cause any significant cytopenias. Rather they grossly spared red blood cells, platelets, and all major immune cells, no transfusions were needed, and immunity remained functionally intact as compared to post traditional conditioning. Additionally, these anti-CD117 antibody-drug conjugates were effective at creating irradiation-free human xenografts in NSG animals. In this setting, depletion of host murine HSCs enabled robust human cord blood HSC engraftment with >48.6±0.28% human total peripheral blood engraftment. Importantly, engraftment was multi-lineage with human myeloid, B-cell and T-cell engraftment which paralleled that of traditional irradiation conditioning, providing the opportunity to study human HSCs in vivo in a non-irradiated setting.
Conclusions: Anti-CD117 antibody-drug conjugates provide the possibility of safe and effective transplantation of both murine and human HSCs without major cytopenias or perturbations to immunity. These agents provide important tools to study murine and human hematopoiesis, but also are likely to become important agents in clinical transplantation. As multiple anti-CD117 antibodies are in development and being tested in clinical trials, such an approach may be rapidly translatable a range of patients with blood and immune diseases including sickle cell anemia, beta thalassemia, immunodeficiencies and HIV.
Conflict of interest:
Agnieszka Czechowicz: Magenta Therapeutics (Scientific Co-Founder, Stockholder, Financial Benefit and/or patents), Editas Medicine (Stockholder, Financial Benefit and/or patents), Global Blood Therapeutics (Stockholder), Decibel Therapeutics (Stockholder) and Third Rock Ventures (Consultant).
Rahul Palchaudhuri: Magenta Therapeutics (Scientific Co-Founder, Salary, Stockholder, Financial Benefit and/or patents)
Amelia Scheck: Nothing to disclose
Yu Hu: Nothing to disclose
Jonathan Hoggatt: Magenta Therapeutics (Scientific Co-Founder, Stockholder, Salary, Financial Benefit and/or patents)
Borja Saez: Nothing to disclose
Michael K. Mansour: Nothing to disclose
Florian Winau: Nothing to disclose
David T. Scadden: Magenta Therapeutics (Co-Founder, Stockholder, Director, Consultant), Fate Therapeutics (Stockholder, Consultant), and Agio Pharmaceuticals (Stockholder, Director).
Derrick J. Rossi: Moderna Therapeutics (Co-Founder, Stockholder, Financial Benefit and/or patents), Intellia Therapeutics (Co-Founder, Stockholder, Consultant), Vor Biopharma (Stockholder, Consultant), Magenta Therapeutics (Co-Founder, Stockholder, Financial Benefit and/or patents), Stelexis Therapeutics (Stockholder, Consultant, Director), Convelo Therapeutics (Stockholder, Consultant, Director).


Assigned speakers:
Assistant Professor Agnieszka Czechowicz , Harvard University , Cambridge , United States

Assigned in sessions:
19.03.2018, 11:00-12:30, Oral Session, OS3, Oral Session 3 - Stem cell and GVHD biology, Room 5C