Many life-threatening and chronic blood diseases are curable by a blood stem cell transplant (SCT). However, patients that undergo SCT can suffer severe and even lethal side effects due in part to the toxic chemotherapy and radiation used to kill a patient’s diseased blood stem cells which allows a donor’s healthy stem cells to take over. Thus, SCT is costly, requires specialized treatment centers, and unavailable to thousands of underserved patients with blood diseases. This project focuses on making SCT safer and more broadly available by engineering proteins, called antibodies (Ab), that can safely replace chemoradiation. Our Abs target a molecule called CD117, present on the surface of normal and cancerous blood stem cells. In prior studies funded by CIRM, this team developed the first anti-CD117 Ab to treat SCT patients. Several clinical trials are now testing the Ab and showing promising results. Here we sought to develop ‘next gen’ anti-CD117 Abs that more potently eradicate cancer stem cells.  We engineered novel Ab constructs that bind CD117 and receptors on immune cells to bring them to kill diseased cells. We made several (>15) constructs and tested them in cell culture studies to measure their ability to enhance killing of target leukemia cells. We chose two constructs with the highest killing activity for further testing in specialized mice implanted with diseased human blood stem cells.  These studies in mice test the safety and ability of the constructs to work in living organisms which are needed to show the construct can be an effective treatment. We will select the best construct for the next steps in development.  To advance this program we will apply for further CIRM funding and to other government and non-profit agencies that support translational research. By reducing the dangers of SCT we hope to make this curative therapy easier and safer to deliver thus making SCT use more equitable for a diverse population of Californians and the world.