Effect of unlabelled monoclonal antibodies on the biodistribution of 111In-labelled anti-prostate-specific acid phosphatase monoclonal antibodies in the mouse model.
In order to optimize methods developed for the radioimaging of prostatic cancer, the effect of unlabelled monoclonal antibodies (MoAbs) on the biodistribution of 111In-labelled MoAbs was studied in nude mice carrying human prostatic cancer xenografts (PC-82). Since the intact IgG and its F(ab')2 fragment have different clearance patterns from the blood, we also studied which of these antibody forms is preferable for use as the unlabelled antibody, when injected prior to, simultaneously with, or following the injection of the labelled antibody. Due to their faster blood clearance, F(ab')2 fragments displayed higher tumour-to-blood ratios than the corresponding anti-prostate-specific acid phosphatase (anti-PAP) IgG1. However, tumour-to-blood ratios increased when the amount of the labelled anti-PAP-IgG1 was increased (from 10 micrograms to 25 micrograms) and the biodistribution measurements were carried out after a prolonged period (216 h). When a combination of labelled IgG1 (1, 10 micrograms) and unlabelled IgG1 (200 micrograms-300 micrograms) was used, tumour-to-blood ratios could not be improved. Contrary to what was observed with the intact IgG1, labelled F(ab')2 fragments did not display a dose-dependent accumulation in the tumour. A combination of labelled F(ab')2 fragments and unlabelled IgG1 resulted in a slight increase in tumour-to-blood ratios, but the administration of labelled F(ab')2 fragments with unlabelled F(ab')2 fragments resulted in a significant decrease (p = 0.04) in tumour-to-blood ratios. Liver-to-blood ratios could be decreased by using either a combination of unlabelled and labelled IgG1 (at ratios of 30:1, or 200:1), or a combination of unlabelled IgG1 and labelled F(ab')2 fragments (at ratios of 50:1, or 100:1), or a combination of the unlabelled and labelled F(ab')2 fragments (at a ratio of 50:1). The decrease of liver-to-blood ratios was independent of the mode of administration of the unlabelled substances. A "rinse" with an additional dose of unlabelled IgG1, 24 h before the sacrifice, resulted in even lower liver-to-blood ratios. The results obtained from this study suggest that, of the combinations investigated, to increase tumour-to-blood ratios and decrease liver-to-blood ratios thereby improving the radioimaging of prostatic cancer, the best one consists of 111In-labelled anti-PAP-F(ab')2 fragments and unlabelled anti-PAP-IgG1.
Peräalä-Heape
M
M
Biocenter, University of Oulu, Finland.
Vihko
P
P
Vihko
R
R
D000135:Acid Phosphatase / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007205:Indium Radioisotopes; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D000135:Acid Phosphatase