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Nat Commun. 2019 Feb 6;10(1):617. doi: 10.1038/s41467-018-08201-x.

Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation.

Czechowicz A1,2,3,4,5,6,7, Palchaudhuri R8,9,10,11,12, Scheck A13,14,8,9,15,16, Hu Y13, Hoggatt J8,9,10, Saez B8,9,10,17, Pang WW16,18,19,20, Mansour MK8,9,10,21, Tate TA8,9,10, Chan YY15,16, Walck E15,16, Wernig G16,22, Shizuru JA16,19,20, Winau F13, Scadden DT23,24,25, Rossi DJ26,27,28,29.

Author information

1
Program in Cellular and Molecular Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, 02115, USA. aneeshka@stanford.edu.
2
Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA. aneeshka@stanford.edu.
3
Department of Pediatrics, Division of Hematology/Oncology, Harvard Medical School, Boston, MA, 02115, USA. aneeshka@stanford.edu.
4
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA. aneeshka@stanford.edu.
5
Harvard Stem Cell Institute, Cambridge, MA, 02138, USA. aneeshka@stanford.edu.
6
Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA. aneeshka@stanford.edu.
7
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA. aneeshka@stanford.edu.
8
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
9
Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.
10
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
11
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.
12
Magenta Therapeutics, Cambridge, MA, 02139, USA.
13
Program in Cellular and Molecular Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, 02115, USA.
14
Department of Pediatrics, Division of Hematology/Oncology, Harvard Medical School, Boston, MA, 02115, USA.
15
Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
16
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
17
Center For Applied Medical Research, Pamplona, 31008, Spain.
18
Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
19
Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, 94305, USA.
20
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA.
21
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, 02114, USA.
22
Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
23
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA. david_scadden@harvard.edu.
24
Harvard Stem Cell Institute, Cambridge, MA, 02138, USA. david_scadden@harvard.edu.
25
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA. david_scadden@harvard.edu.
26
Program in Cellular and Molecular Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, 02115, USA. derrick.rossi@childrens.harvard.edu.
27
Department of Pediatrics, Division of Hematology/Oncology, Harvard Medical School, Boston, MA, 02115, USA. derrick.rossi@childrens.harvard.edu.
28
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA. derrick.rossi@childrens.harvard.edu.
29
Harvard Stem Cell Institute, Cambridge, MA, 02138, USA. derrick.rossi@childrens.harvard.edu.

Abstract

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for blood and immune diseases with potential for many settings beyond current standard-of-care. Broad HSCT application is currently precluded largely due to morbidity and mortality associated with genotoxic irradiation or chemotherapy conditioning. Here we show that a single dose of a CD117-antibody-drug-conjugate (CD117-ADC) to saporin leads to > 99% depletion of host HSCs, enabling rapid and efficient donor hematopoietic cell engraftment. Importantly, CD117-ADC selectively targets hematopoietic stem cells yet does not cause clinically significant side-effects. Blood counts and immune cell function are preserved following CD117-ADC treatment, with effective responses by recipients to both viral and fungal challenges. These results suggest that CD117-ADC-mediated HSCT pre-treatment could serve as a non-myeloablative conditioning strategy for the treatment of a wide range of non-malignant and malignant diseases, and might be especially suited to gene therapy and gene editing settings in which preservation of immunity is desired.

PMID:
30728354
PMCID:
PMC6365495
DOI:
10.1038/s41467-018-08201-x
[Indexed for MEDLINE]
Free PMC Article

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