title: Biodistributions, myelosuppression, and toxicities in mice treated with an anti-CD45 antibody labeled with the alpha-emitting radionuclides bismuth-213 or astatine-211.
abstract: We previously investigated the potential of targeted radiotherapy using a bismuth-213 ((213)Bi)-labeled anti-CD45 antibody to replace total body irradiation as conditioning for hematopoietic cell transplantation in a canine model. Although this approach allowed sustained marrow engraftment, limited availability, high cost, and short half-life of (213)Bi induced us to investigate an alternative alpha-emitting radionuclide, astatine-211 ((211)At), for the same application. Biodistribution and toxicity studies were conducted with conjugates of the anti-murine CD45 antibody 30F11 with either (213)Bi or (211)At. Mice were injected with 2 to 50 muCi on 10 microg or 20 muCi on 2 or 40 microg of 30F11 conjugate. Biodistribution studies showed that the spleen contained the highest concentration of radioactivity, ranging from 167 +/- 23% to 417 +/- 109% injected dose/gram (% ID/g) after injection of the (211)At conjugate and 45 +/- 9% to 166 +/- 11% ID/g after injection of the (213)Bi conjugate. The higher concentrations observed for (211)At-labeled 30F11 were due to its longer half-life, which permitted better localization of isotope to the spleen before decay. (211)At was more effective at producing myelosuppression for the same quantity of injected radioactivity. All mice injected with 20 or 50 muCi (211)At, but none with the same quantities of (213)Bi, had lethal myeloablation. Severe reversible acute hepatic toxicity occurred with 50 muCi (213)Bi, but not with lower doses of (213)Bi or with any dose of (211)At. No renal toxicity occurred with either radionuclide. The data suggest that smaller quantities of (211)At-labeled anti-CD45 antibody are sufficient to achieve myelosuppression and myeloablation with less nonhematologic toxicity compared with (213)Bi-labeled antibody.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Nakamae
authors.forename: D Scott
authors.initials: DS
authors.lastname: Wilbur
authors.forename: Donald K
authors.initials: DK
authors.lastname: Hamlin
authors.forename: Monica S
authors.initials: MS
authors.lastname: Thakar
authors.forename: Erlinda B
authors.initials: EB
authors.lastname: Santos
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Fisher
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Kenoyer
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Sandmaier
mesh_terms: D000512:Alpha Particles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001246:Astatine / Q000493:pharmacokinetics* / Q000633:toxicity; D001729:Bismuth / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D000922:Immunotoxins / Q000276:immunology / Q000493:pharmacokinetics* / Q000633:toxicity; D007553:Isotope Labeling; D007674:Kidney Diseases / Q000209:etiology; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008107:Liver Diseases / Q000209:etiology; D051379:Mice; D008807:Mice, Inbred BALB C; D011833:Radiation Injuries, Experimental / Q000209:etiology; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods; D011868:Radioisotopes / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D011868:Radioisotopes; D017493:Leukocyte Common Antigens; D001729:Bismuth; D001246:Astatine