Anti-CD45 radioimmunotherapy using 211At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model

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 limite...

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Veröffentlicht in:Blood 2013-05, Vol.121 (18), p.3759-3767
Hauptverfasser: Orozco, Johnnie J., Bäck, Tom, Kenoyer, Aimee, Balkin, Ethan R., Hamlin, Donald K., Wilbur, D. Scott, Fisher, Darrell R., Frayo, Shani L., Hylarides, Mark D., Green, Damian J., Gopal, Ajay K., Press, Oliver W., Pagel, John M.
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Sprache:eng
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Zusammenfassung: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 211At, which has a higher energy profile and shorter path length. We evaluated the efficacy and toxicity of anti-CD45 RIT using 211At in a disseminated murine AML model. Biodistribution studies in leukemic SJL/J mice showed excellent localization of 211At-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, 211At-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 211At-anti-CD45 RIT in conjunction with HSCT may be a promising therapeutic option for AML. •Astatination of anti-CD45 antibody via a closo-decaborate compound yields a stable conjugate that targets radiation to hematologic organs.•211At-anti-CD45 radioimmunotherapy combined with bone marrow transplantation prolongs survival in a disseminated murine leukemia model.
ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood-2012-11-467035