Effect of conjugation on the biodistribution of 111In-labelled anti-PAP and anti-PSA monoclonal antibodies examined in nude mice with PC-82 human tumor xenografts.
The effect of conjugation on the biodistribution of 111In-labelled antibodies was studied in nude mice carrying human prostatic cancer xenografts (PC-82). Two monoclonal antibodies and their fragments raised against human prostate-specific acid phosphatase (PAP) and prostate-specific antigen (PSA) were used. We used the cyclic anhydride of DTPA (CA-DTPA) as a chelating agent, or, alternatively, 1-(p-aminobenzyl)diethylenetriaminepentaacetic acid (NH2-Bz-DTPA) was attached as a linker to the carbohydrate components of the parent molecules. The conjugation method, the amount of circulating antigen and the size of the antibody component affected the blood clearance of the labelled derivatives. F(ab')2 fragments displayed a faster blood clearance than the corresponding derivatives of intact IgG1s. Aminobenzyl derivatives of anti-PAP-IgG1 showed a faster blood clearance than the corresponding CA-DTPA derivatives, but, in the case of derivatives of anti-PSA-IgG1, this was less clear, possibly due to the high PSA concentrations in the mouse sera. All the derivatives studied accumulated in the liver independently of the size of the antibody derivative, most probably due to the formation of antigen-antibody complexes. All CA-DTPA derivatives showed a higher kidney accumulation than the corresponding aminobenzyl derivatives. CA-DTPA-anti-PAP-F(ab')2 fragments showed a higher kidney uptake than the corresponding anti-PSA-F(ab')2 derivatives, since a large fraction of the latter are complexed with circulating antigen, thereby slowing down its reabsorption by the kidney. In addition, the lower kidney accumulation for anti-PSA-F(ab')2 fragments might be, at least partly, due to the electronegative charge of the molecule.(ABSTRACT TRUNCATED AT 250 WORDS)
Perälä-Heape
M
M
Biocenter, University of Oulu, Finland.
Vihko
P
P
Pelkonen
I
I
Laine
A
A
Vihko
R
R
D000135:Acid Phosphatase / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000951:Antigens, Neoplasm / Q000276:immunology*; D002460:Cell Line; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000302:isolation & purification; D007205:Indium Radioisotopes / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000276:immunology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000378:metabolism*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D007140:Immunoglobulin Fab Fragments; D007205:Indium Radioisotopes; D007527:Isoenzymes; D000135:Acid Phosphatase; D017430:Prostate-Specific Antigen