Preclinical studies targeting normal and leukemic hematopoietic cells with Yttrium-90-labeled anti-CD45 antibody in vitro and in vivo in nude mice.
A study was undertaken to investigate the suitability of using a high affinity (Kd = 1.1 nM) anti-CD45 monoclonal antibody for delivering the high energy beta-particle emitting isotope (90)Y to lymphohematopoietic target cells in vivo. The antibody, AHN-12, recognized the tyrosine phosphatase CD45 expressed on the surface of normal and malignant hematopoietic cells and studies showed that it reacted with both CD45-expressing normal peripheral blood cells and leukemia cells from patients. The antibody was readily labeled with (90)Y using the highly stable chelate 1B4M-DTPA and the radioimmunoconjugate was designated (90)Y-anti-CD45. The agent selectively bound to CD45(+) B cell line Daudi, but not CD45(-) control cells and significantly (p = 0.007) more bound to Daudi tumors growing in athymic nude mice than did a control non-reactive antibody. Moreover, biodistribution data correlated well to an anti-Daudi effect observed against established tumors in nude mice. The effect was dose dependent and irreversible with the best results in mice receiving a single dose of 137 microCi (90)Y-anti-CD45. These mice displayed a significantly (p < 0.0095) better anti-tumor effect than a control (90)Y-labeled antibody and survived over 135 days with no evidence of tumor. Histology studies showed no significant injury to kidney, liver, or small intestine even at 254 microCi, the highest dose tested. Because radiolabeled anti-CD45 antibody can be used to deliver radiation selectively to lymphohematopoietic tissue, these data indicate that this agent may be used to improve treatment of hematopoietic malignancies, particularly leukemia and lymphoma, when combined with hematopoietic stem cell transplantation in a future clinical trial.
Vallera
D A
DA
University of Minnesota Cancer Center, Department of Therapeutic Radiology-Radiation Oncology, Minneapolis 55455, USA. valle001@umn.edu
Elson
M
M
Brechbiel
M W
MW
Dusenbery
K E
KE
Burns
L J
LJ
Skubitz
K M
KM
Jaszcz
W B
WB
Ramsay
N K
NK
Panoskaltsis-Mortari
A
A
Kuroki
D W
DW
Wagner
J E
JE
Kersey
J H
JH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002051:Burkitt Lymphoma / Q000532:radiotherapy*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006412:Hematopoietic Stem Cells / Q000528:radiation effects*; D006801:Humans; D007205:Indium Radioisotopes; D007951:Leukemia, Myeloid / Q000532:radiotherapy*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D004369:Pentetic Acid; D016499:Radioimmunotherapy; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes; D004369:Pentetic Acid; D017493:Leukocyte Common Antigens