CD45-Targeted Astatine-211 Conditioning for Autologous Gene Therapy
Radtke S, Laszlo GS, Swing K, et al. [211At[Astatine-Based Conditioning With a Humanized CD45 Antibody for Autologous Hematopoietic Stem Cell Gene Therapy. Blood. 2026; (doi: 10.1182/blood.2026033789).
Based on preclinical evidence, researchers believe CD45-directed radioimmunotherapy (RIT) with astatine-211 (211At) may have utility as a conditioning regimen prior to autologous gene therapy. Ablation of resident hematopoietic stem cells is required before gene-modified hematopoietic stem/progenitor cells (HSPCs) can be transplanted, but total body irradiation (TBI) and other traditional myeloablative conditioning methods are associated with non-hematologic toxicities. As an alternative, a humanized CD45 antibody labeled with 211At was evaluated in nonhuman primates. The approach facilitated engraftment of gene-edited autologous HSPCs at levels exceeding those achieved with high-dose TBI, and the four animals treated with CD45-211At experienced rapid recovery of neutrophils and platelets while showing no signs of non-hematopoietic toxicities. A single-cell sequencing assay analysis also suggested complete replacement of the bone marrow stem cell compartment and unbiased contribution of multiplex-edited HSPCs to all mature lineages in the blood, supporting successful stem cell replacement following autologous HSPC gene therapy.