Immunotherapy for rapid bone marrow conditioning and leukemia depletion that allows efficient hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure to treat hematopoietic disorders. Current bone marrow conditioning protocols create space for healthy donor stem cells by employing irradiation and/or chemotherapy, but carry severe toxicities, resulting in significant morbidity, mortality and substantial long-term complications. To develop a low-toxicity solution, we generated a bi-specific T-cell engager (BTCE) that targets CD117, an abundantly expressed receptor on hematopoietic stem and progenitor cells (HSPC) and leukemia-initiating cells (LICs). We show that the CD117×CD3 BTCE efficiently depletes in vitro and in vivo HSPCs and LICs. The CD117×CD3 BTCE was not toxic and facilitates highly efficient engraftment of human allogenic donor CD34+cells in humanized mice, thereby restoring hematopoiesis in vivo in both normal and leukemia-bearing humanized mice. We demonstrate here that a potent CD117×CD3 BTCE enables rapid HSCT in both benign and malignant conditions.