title: Anti-CD45 radioimmunotherapy using (211)At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model.
abstract: Despite aggressive chemotherapy combined with hematopoietic stem cell transplantation (HSCT), many patients with acute myeloid leukemia (AML) relapse. Radioimmunotherapy (RIT) using monoclonal antibodies labeled with β-emitting radionuclides has been explored to reduce relapse. β emitters are limited by lower energies and nonspecific cytotoxicity from longer path lengths compared with α emitters such as (211)At, which has a higher energy profile and shorter path length. We evaluated the efficacy and toxicity of anti-CD45 RIT using (211)At in a disseminated murine AML model. Biodistribution studies in leukemic SJL/J mice showed excellent localization of (211)At-anti-murine CD45 mAb (30F11) to marrow and spleen within 24 hours (18% and 79% injected dose per gram of tissue [ID/g], respectively), with lower kidney and lung uptake (8.4% and 14% ID/g, respectively). In syngeneic HSCT studies, (211)At-B10-30F11 RIT improved the median survival of leukemic mice in a dose-dependent fashion (123, 101, 61, and 37 days given 24, 20, 12, and 0 µCi, respectively). This approach had minimal toxicity with nadir white blood cell counts >2.7 K/µL 2 weeks after HSCT and recovery by 4 weeks. These data suggest that (211)At-anti-CD45 RIT in conjunction with HSCT may be a promising therapeutic option for AML.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Johnnie J
authors.initials: JJ
authors.lastname: Orozco
authors.forename: Tom
authors.initials: T
authors.lastname: Bäck
authors.forename: Aimee
authors.initials: A
authors.lastname: Kenoyer
authors.forename: Ethan R
authors.initials: ER
authors.lastname: Balkin
authors.forename: Donald K
authors.initials: DK
authors.lastname: Hamlin
authors.forename: D Scott
authors.initials: DS
authors.lastname: Wilbur
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Fisher
authors.forename: Shani L
authors.initials: SL
authors.lastname: Frayo
authors.forename: Mark D
authors.initials: MD
authors.lastname: Hylarides
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Green
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Gopal
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001246:Astatine / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D007938:Leukemia / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D051379:Mice; D009362:Neoplasm Metastasis; D016499:Radioimmunotherapy / Q000379:methods*; D016019:Survival Analysis; D014018:Tissue Distribution; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D017493:Leukocyte Common Antigens; D001246:Astatine