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

Agnieszka Czechowicz (), Rahul Palchaudhuri, Amelia Scheck, Yu Hu, Jonathan Hoggatt, Borja Saez, Wendy W. Pang, Michael K. Mansour, Tiffany A. Tate, Yan Yi Chan, Emily Walck, Gerlinde Wernig, Judith A. Shizuru, Florian Winau, David T. Scadden () and Derrick J. Rossi ()
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Agnieszka Czechowicz: Boston Children’s Hospital
Rahul Palchaudhuri: Harvard University
Amelia Scheck: Boston Children’s Hospital
Yu Hu: Boston Children’s Hospital
Jonathan Hoggatt: Harvard University
Borja Saez: Harvard University
Wendy W. Pang: Stanford University School of Medicine
Michael K. Mansour: Harvard University
Tiffany A. Tate: Harvard University
Yan Yi Chan: Stanford University School of Medicine
Emily Walck: Stanford University School of Medicine
Gerlinde Wernig: Stanford University School of Medicine
Judith A. Shizuru: Stanford University School of Medicine
Florian Winau: Boston Children’s Hospital
David T. Scadden: Harvard University
Derrick J. Rossi: Boston Children’s Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08201-x

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