Effective Multi-lineage Engraftment in a Mouse Model of Fanconi Anemia Using Non-genotoxic Antibody-Based Conditioning

Meera A. Srikanthan, Olivier Humbert, Kevin G. Haworth, Christina Ironside, Yogendra S. Rajawat, Bruce R. Blazar, Rahul Palchaudhuri, Anthony E. Boitano, Michael P. Cooke, David T. Scadden, Hans Peter Kiem

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Conditioning chemotherapy is used to deplete hematopoietic stem cells in the recipient's marrow, facilitating donor cell engraftment. Although effective, a major issue with chemotherapy is the systemic genotoxicity that increases the risk for secondary malignancies. Antibody conjugates targeting hematopoietic cells are an emerging non-genotoxic method of opening the marrow niche and promoting engraftment of transplanted cells while maintaining intact marrow cellularity. Specifically, this platform would be useful in diseases associated with DNA damage or cancer predisposition, such as dyskeratosis congenita, Schwachman-Diamond syndrome, and Fanconi anemia (FA). Our approach utilizes antibody-drug conjugates (ADC) as an alternative conditioning regimen in an FA mouse model of autologous transplantation. Antibodies targeting either CD45 or CD117 were conjugated to saporin (SAP), a ribosomal toxin. FANCA knockout mice were conditioned with either CD45-SAP or CD117-SAP prior to receiving whole marrow from a heterozygous healthy donor. Bone marrow and peripheral blood analysis revealed equivalent levels of donor engraftment, with minimal toxicity in ADC-treated groups as compared with cyclophosphamide-treated controls. Our findings suggest ADCs may be an effective conditioning strategy in stem cell transplantation not only for diseases where traditional chemotherapy is not tolerated, but also more broadly for the field of blood and marrow transplantation.

Original languageEnglish (US)
Pages (from-to)455-464
Number of pages10
JournalMolecular Therapy Methods and Clinical Development
StatePublished - Jun 12 2020

Bibliographical note

Funding Information:
We thank Helen Crawford for help preparing and formatting this manuscript and the figures. We thank Jerry Chen for assistance with mouse injections, health checks, and maintaining the Fanca mouse breeding colony. We also thank Sarah Weitz for assistance maintaining the Fanca mouse breeding colony, Martin Wohlfahrt and Madison Norton for lentiviral production, Amanda Koehne for veterinarian histopathology expertise, and the Comparative Medicine staff at Fred Hutch for support with vivarium maintenance. H.-P.K. is a Markey Molecular Medicine Investigator and received support as the inaugural recipient of the Jose Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Endowed Chair for Stem Cell and Gene Therapy . This work was supported in part by H.-P.K ’s endowment fund , material support from Magenta Therapeutics , as well as by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number P01HL122171 and R01HL147324 . This research was also funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, which had no involvement in the in-study design; the collection, analysis, and interpretation of data; the writing of the report; nor in the decision to submit the article for publication.

Funding Information:
H.-P.K. is a consultant for Rocket Pharma and Homology Medicine. A.E.B., R.P., and M.P.C. are full-time salaried employees of Magenta Therapeutics. D.T.S. and B.R.B. are members of the Scientific Advisory Board of Magenta. B.R.B. receives remuneration as an advisor to Kamon Pharmaceuticals, Inc., Five Prime Therapeutics Inc., Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics; receives research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Inc., Abbvie Inc., BlueRock Therapeutics Leukemia and Lymphoma Society, Childrens’ Cancer Research Fund, and KidsFirst Fund; and is a co-founder of Tmunity.

Publisher Copyright:
© 2020


  • CD117
  • Fanconi anemia
  • Fanconi anemia gene therapy
  • non-genotoxic conditioning
  • saporin


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