α-Imaging Confirmed Efficient Targeting of CD45-Positive Cells After 211At-Radioimmunotherapy for Hematopoietic Cell Transplantation.
α-radioimmunotherapy targeting CD45 may substitute for total-body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (mAb; CA12.10C12) protein dose for (211)At-radioimmunotherapy, extending the analysis to include intraorgan (211)At activity distribution and α-imaging-based small-scale dosimetry, along with immunohistochemical staining.


METHODS
Eight normal dogs were injected with either a 0.75 (n = 5) or 1.00 (n = 3) mg/kg dose of (211)At-B10-CA12.10C12 (11.5-27.6 MBq/kg). Two were euthanized and necropsied 19-22 h after injection, and 6 received autologous HCT 3 d after (211)At-radioimmunotherapy, after lymph node and bone marrow biopsies at 2-4 and/or 19 h after injection. Blood was sampled to study toxicity and clearance; CD45 targeting was evaluated by flow cytometry. (211)At localization and small-scale dosimetry were assessed using two α-imaging systems: an α-camera and an ionizing-radiation quantum imaging detector (iQID) camera.


RESULTS
(211)At uptake was highest in the spleen (0.31-0.61% injected activity [%IA]/g), lymph nodes (0.02-0.16 %IA/g), liver (0.11-0.12 %IA/g), and marrow (0.06-0.08 %IA/g). Lymphocytes in blood and marrow were efficiently targeted using either mAb dose. Lymph nodes remained unsaturated but displayed targeted (211)At localization in T lymphocyte-rich areas. Absorbed doses to blood, marrow, and lymph nodes were estimated at 3.1, 2.4, and 3.4 Gy/166 MBq, respectively. All transplanted dogs experienced transient hepatic toxicity. Liver enzyme levels were temporarily elevated in 5 of 6 dogs; one treated with 1.00 mg mAb/kg developed ascites and was euthanized 136 d after HCT.


CONCLUSIONS
(211)At-anti-CD45 radioimmunotherapy with 0.75 mg mAb/kg efficiently targeted blood and marrow without severe toxicity. Dosimetry calculations and observed radiation-induced effects indicated that sufficient (211)At-B10-CA12.10C12 localization was achieved for efficient conditioning for HCT.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington sfrost@fredhutch.org.
Sofia H L
SH
Frost
Pacific Northwest National Laboratory, Richland, Washington College of Optical Sciences, University of Arizona, Tucson, Arizona.
Brian W
BW
Miller
Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Tom A
TA
Bäck
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Erlinda B
EB
Santos
Department of Radiation Oncology, University of Washington, Seattle, Washington.
Donald K
DK
Hamlin
Comparative Medicine Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, Washington; and.
Sue E
SE
Knoblaugh
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Shani L
SL
Frayo
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Aimee L
AL
Kenoyer
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington.
Rainer
R
Storb
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington.
Oliver W
OW
Press
Department of Radiation Oncology, University of Washington, Seattle, Washington.
D Scott
DS
Wilbur
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington.
John M
JM
Pagel
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington.
Brenda M
BM
Sandmaier
D000512:Alpha Particles; D000818:Animals; D001201:Ascites / Q000000981:diagnostic imaging; D001246:Astatine / Q000009:adverse effects / Q000493:pharmacokinetics*; D001706:Biopsy; D001853:Bone Marrow / Q000000981:diagnostic imaging; D004285:Dogs; D016503:Drug Delivery Systems; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens; D008198:Lymph Nodes / Q000000981:diagnostic imaging; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000493:pharmacokinetics*; D013154:Spleen / Q000000981:diagnostic imaging; D013601:T-Lymphocytes / Q000000981:diagnostic imaging; D014018:Tissue Distribution
D019275:Radiopharmaceuticals; D017493:Leukocyte Common Antigens; D001246:Astatine
211At; CD45; alpha imaging; lymphoma; radioimmunotherapy