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

Publication Type:

Journal Article

Source:

Blood, Volume 119, Issue 5, p.1130-1138 (2012)

Keywords:

2012, Alpha Particles, Animals, Antibodies, Monoclonal, Blood Donors, Boron Compounds/chemistry, CD45, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Cultured, Dec, December 2011, Dogs, Dose-Response Relationship, Drug, Experimental Histopathology Core Facility, Hematologic Neoplasms, hematopoietic stem cell transplantation, Radioimmunotherapy, Shared Resources, Specialized Pathology Core Facility, Transplantation Conditioning, Transplantation, Homologous

Abstract:

To reduce toxicity associated with external γ-beam radiation, we investigated radioimmunotherapy (RIT) with an anti-CD45 monoclonal antibody (mAb) labeled with the α emitter, astatine 211 ((211)At), as a conditioning regimen in dog leukocyte antigen (DLA)-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100-618 µCi/kg (211)At-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 (211)At doses ≤ 405-µCi/kg. Higher doses of (211)At induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155-625 µCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) prior to HCT with DLA-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/µl), lymphopenia (0-270 cells/µl) and thrombocytopenia (1500-6560 platelets/µl) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell (MNC) chimerism (19-58%), while one dog treated with the lowest (211)At dose (155 µCi/kg) had low donor MNC 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 (211)At-labeled anti-CD45 mAb is safe and efficacious, and provides a platform for future clinical trials of nonmyeloablative transplantation with RIT-based conditioning.