Selective radiation of hematolymphoid tissue delivered by anti-CD45 antibody.
The ability to deliver radiation selectively to lymphohematopoietic tissues may have utility in conditions treated by myeloablative regimens followed by bone marrow transplantation. Since the CD45 antigen is the most broadly expressed of hematopoietic antigens, we examined the biodistribution of radiolabeled anti-CD45 monoclonal antibodies in normal mice. Trace 125I or 131I-labeled monoclonal antibodies 30G12 (rat IgG2a), 30F11 (rat IgG2b), and F(ab')2 fragments of 30F11 were injected i.v. at doses of 5 to 1000 micrograms. For both intact antibodies, a higher percentage of injected dose/g (% ID/g tissue) in blood was achieved with higher antibody doses. However, as the dose of antibody was increased, the % ID/g in the target organs of spleen, marrow, and lymph nodes decreased. At doses between 5 and 10-micrograms, % ID/g in these tissues exceeded that in lung, the normal organ with the highest concentration of radiolabel. In contrast, thymus was the only hematopoietic organ in which the % ID/g increased with increasing antibody dose, although at high dose the % ID/g was still far below that achieved in the other hematopoietic organs. Antibody 30F11 F(ab')2 fragments were cleared more quickly than intact antibody from blood and from both target and nontarget organs, although the relationship between increasing antibody dose and decreasing % ID/g in spleen, marrow, and lymph nodes was observed. The time-activity curves for each dose of antibody were used to calculate estimates of radiation absorbed dose to each organ. At the 10-micrograms dose of 30G12, the spleen was estimated to receive a radiation dose that was 13 times more than lung, the lymph nodes 3 to 4 times more, and the bone marrow 3 times more than lung. For each antibody fragment dose, the radiation absorbed dose per MBq 131I administered was lower because the residence times of the fragments were shorter than those of the intact antibody. Thus these estimates suggested that the best "therapeutic ratio" of radiation delivered to target organ as compared to lung was achieved with lower doses of intact antibody. We have demonstrated that radiolabeled anti-CD45 monoclonal antibodies can deliver radiation to lymphohematopoietic tissues with relative selectivity and that the relative uptake and retention in different hematolymphoid tissues change with increasing antibody dose.
Matthews
D C
DC
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104.
Badger
C C
CC
Fisher
D R
DR
Hui
T E
TE
Nourigat
C
C
Appelbaum
F R
FR
Martin
P J
PJ
Bernstein
I D
ID
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D015703:Antigens, CD / Q000276:immunology*; D001853:Bone Marrow / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D006649:Histocompatibility Antigens / Q000276:immunology*; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics*; D017493:Leukocyte Common Antigens; D007962:Leukocytes / Q000378:metabolism / Q000528:radiation effects; D008198:Lymph Nodes / Q000378:metabolism / Q000528:radiation effects; D008221:Lymphoid Tissue / Q000378:metabolism* / Q000528:radiation effects; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D011829:Radiation Dosage; D013154:Spleen / Q000378:metabolism / Q000528:radiation effects; D013950:Thymus Gland / Q000378:metabolism / Q000528:radiation effects; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D006649:Histocompatibility Antigens; D007140:Immunoglobulin Fab Fragments; D007457:Iodine Radioisotopes; D017493:Leukocyte Common Antigens