Durable donor engraftment after radioimmunotherapy using α-emitter astatine-211-labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation

To reduce toxicity associated with external gamma-beam radiation, we investigated radioimmunotherapy with an anti-CD45 mAb labeled with the alpha-emitter, astatine-211 (At-211), as a conditioning regimen in dog leukocyte antigen-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100 to 618 mu Ci/kg At-211-labeled anti-CD45 mAb (0.5 mg/kg) without HCT rescue demonstrated dose-dependent myelosuppression with subsequent autologous recovery, and transient liver toxicity in dogs treated with At-211 doses less than or equal to 405 mu Ci/kg. Higher doses of At-211 induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155 to 625 mu Ci/kg At-211-labeled anti-CD45 mAb (0.5 mg/kg) before HCT with dog leukocyte antigen-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/mu L), lymphopenia (0-270 cells/mu L), and thrombocytopenia (1500-6560 platelets/mu L) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell chimerism (19%-58%), whereas 1 dog treated with the lowest At-211 dose (155 mu Ci/kg) had low donor mononuclear cell chimerism (5%). At the end of follow-up (18-53 weeks), only transient liver toxicity and no renal toxicity had been observed. In conclusion, conditioning with At-211-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning. (Blood. 2012;119(5):1130-1138)