211Astatine-CD123 Radioimmunotherapy for Cancer (Stem) Cell-Directed Treatment of Acute Leukemia
Roland Walter
MD PhDFred Hutchinson Cancer Center
Project Term: July 1, 2023 - June 30, 2026
Because acute leukemias are very sensitive to radiation, radioisotopes are ideal payloads to arm antibodies against these difficult-to-cure, aggressive blood cancers. Here, we will develop fully human anti-CD123 antibodies carrying the highly potent alpha-emitter astatine-211 (211At) as a new therapy for acute leukemia. CD123 is broadly displayed on acute leukemia cells in most patients and overexpressed on leukemic stem cells but is only found on a small subset of normal blood cells, enabling the use of 211At-CD123 radioimmunotherapy in the transplant and non-transplant setting with limited toxicities to normal tissues.
Despite aggressive multiagent chemotherapies, bone marrow transplantation, and several new drugs, acute leukemias remain difficult to treat. Even today, a majority of patients are expected to die of their disease. There is thus a critical need for effective new treatments for these aggressive blood cancers. While acute leukemias are genetically very diverse, they have in common that they are highly sensitive to ionizing radiation. Because it is not safe to expose a patient’s normal tissues to radiation, our center and others have developed a technology called radioimmunotherapy. Radioimmunotherapy uses antibodies, Y-shaped proteins that work like a lock and key and can recognize a unique part of cancer cells, to deliver a radiation payload directly to the leukemia cells within the patient while sparing other cells. Building on this pioneering work, we now plan to improve this technology by using the radioactive isotope, astatine-211, as payload. We focus on this isotope because it delivers a much higher amount of radiation than isotopes used previously and has ideal half-life properties for use in patients. Although it has a much higher potency, astatine-211 is safer and less toxic than other radioactive elements because it unloads its radiation cargo over a much shorter distance of only a few cell diameters, which will minimize radiation of healthy tissue surrounding the leukemia cells. As a novelty of our research, we will couple astatine-211 to antibodies we developed that recognize a protein called CD123. CD123 is found on the surface of acute leukemia cells in most patients, including underlying leukemia stem cells (the type of cells responsible for the propagation of the leukemia), making it an ideal target for this type of therapy. Our preliminary data in leukemia mouse models demonstrate that CD123-targeted radioimmunotherapy with astatine-211 indeed has high anti-leukemia efficacy. We are now poised to develop this novel radioimmunotherapy for patient application and use protein engineering tools to maximize the selective delivery of astatine-211 to CD123-positive leukemia cells while, at the same time, further minimize radiation delivery to normal cells. Expected results from the planned studies will put us in an excellent position to rapidly bring our innovative treatment forward to the clinic. Important for this translation, our group has the infrastructure and expertise to bring astatine-211-based radioimmunotherapy from the laboratory to early phase testing in patients with acute leukemia.