Development of [211At]astatine-based anti-CD123 radioimmunotherapy for acute leukemias and other CD123+ malignancies.

Abstract

Radioimmunotherapy (RIT) has long been pursued to improve outcomes in acute leukemia and higher-risk myelodysplastic syndrome. Of increasing interest are alpha particle-emitting radionuclides such as astatine-211 (211At) as they deliver large amounts of radiation over just a few cell diameters, enabling efficient and selective target cell kill. Here, we developed 211At-based RIT targeting CD123, an antigen widely displayed on acute leukemia and MDS cells including underlying neoplastic stem cells. We generated and characterized new murine monoclonal antibodies (mAbs) specific for human CD123 and selected four, all of which were internalized by CD123+ target cells, for further characterization. All mAbs could be conjugated to a boron cage, isothiocyanatophenethyl-ureido-closo-decaborate(2-) (B10), and labeled with 211At. CD123+ cell targeting studies in immunodeficient mice demonstrated specific uptake of 211At-labeled anti-CD123 mAbs in human CD123+ MOLM-13 cell tumors in the flank. In mice injected intravenously with MOLM-13 cells or a CD123NULL MOLM-13 subline, a single dose of up to 40 μCi of 211At delivered via anti-CD123 mAb decreased tumor burdens and significantly prolonged survival dose-dependently in mice bearing CD123+ but not CD123− leukemia xenografts, demonstrating potent and target-specific in vivo anti-leukemia efficacy. These data support the further development of 211At-CD123 RIT toward clinical application.