Improved tumor detection by anti-CEA chimeric Fab oligomers with disulfide linkages in a pancreatic-carcinoma-xenograft model.
We have investigated the effect of Fab oligomerization on imaging efficacy in a pancreatic-carcinoma xenograft model in mice. Recombinant mouse/human chimeric Fab of the anticarcinoembryonic antigen (CEA) monoclonal antibody A10, which has been shown to react specifically with gastrointestinal cancers, was used in this study. Fab homo-oligomers (dimers and trimers) were prepared by linkage of chimeric Fab with N-succinimidyl-3-(2-pyridyldithio)-propionate. Oligomers with S-S bonds showed 10-fold higher binding activity against human CEA than Fab, while the binding activity of oligomers was similar to that of F(ab')2. In mice bearing pancreatic-carcinoma xenografts, tumor uptake of S-S oligomers was significantly greater than that of monomeric Fab, while there was no difference in tumor uptake between S-S Fab trimers and F(ab')2. S-S oligomers showed more rapid clearance rates and uniform percolation in the tumor nodules than F(ab')2. At 18 hr after injection, clear scintigraphic detection of the pancreatic-carcinoma tumors was obtained with 123I-labeled S-S Fab dimers. At 24hr, improved tumor imaging was shown for 123I-labeled S-S Fab oligomers with slightly visible uptake in normal tissues, similar to that of F(ab')2. S-S oligomers of chimeric A10 Fab may be useful as rapid diagnostic tools of pancreatic carcinomas.
Kamigaki
T
T
First Department of Surgery, Kobe University School of Medicine, Japan.
Yamamoto
M
M
Ohyanagi
H
H
Ohya
M
M
Kono
A
A
Ohtani
W
W
Narita
Y
Y
Ohkubo
M
M
Ohmura
T
T
Saitoh
Y
Y
D000818:Animals; D001345:Autoradiography; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007457:Iodine Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging*; D016719:Radioimmunodetection; D011993:Recombinant Fusion Proteins; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D002272:Carcinoembryonic Antigen; D007140:Immunoglobulin Fab Fragments; D007457:Iodine Radioisotopes; D011993:Recombinant Fusion Proteins