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

• DOI: 10.1038/s41467-018-08201-x
• Publication Date: 2019-02-06T11:04:47Z
• Authors: 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; Derrick J. Rossi
• Keywords: 0301 basic medicine; Immunoconjugates; Science; Article; Cell Line; Mice; 03 medical and health sciences; Bone Marrow; Neoplasms; Candida albicans; Animals; Humans; Bone Marrow Transplantation; 0303 health sciences; Cell Death; Q; Hematopoietic Stem Cell Transplantation; Materias Investigacion::Ciencias de la Salud::Hematología; Genetic Therapy; Hematopoietic Stem Cells; Tissue Donors; 3. Good health; Mice, Inbred C57BL; Proto-Oncogene Proteins c-kit; Female; :Ciencias de la Salud::Hematología [Materias Investigacion]

AbstractHematopoietic 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.