Pretargeting of carcinoembryonic antigen-expressing tumors with a biologically produced bispecific anticarcinoembryonic antigen x anti-indium-labeled diethylenetriaminepentaacetic acid antibody.
OBJECTIVE
The aim of these studies was to develop a pretargeting strategy for CEA-expressing cancers using biologically produced bispecific monoclonal antibodies (bsMAb). The bsMAbs used in this system have affinity for the carcinoembryonic antigen on the one hand, and for indium-labeled diethylenetriaminepentaacetic acid (DTPA), on the other.


METHODS
Stable quadroma clones producing bsMAb MN-14xDTIn-1 were isolated. LS174T tumor-bearing mice were injected with 1 to 100 microg of bsMAb followed by 1 to 60 ng of an (111)In-labeled bivalent peptide [Ac-Phe-Lys(DTPA)-Tyr-Lys(DTPA)-NH2]. Mice were killed at 24 hours postinjection and the biodistribution of the radiolabel was determined. The biodistribution of diDTPA labeled with four different radionuclides ((111)In, 99mTc, nonresidualizing 125I, and residualizing 125I) was determined at various time points postinjection following pretargeting of LS174T tumors with bsMAb MN-14xDTIn-1.


RESULTS
Optimal tumor targeting was observed when tumors were pretargeted with 10 microg of bsMAb MN-14xDTIn-1 and when 6 ng of a radiolabeled peptide was given 72 hours later. The uptake of the four radiolabels in LS174T tumors at 4 hours postinjection was similar. However, at later time points, the (111)In-label and residualizing 125I-label were better retained in the tumor than the nonresidualizing 125I label. Although the absolute uptake in the tumor (in terms of percentage of injected dose per gram of tissue) was 5-fold lower than the uptake obtained with directly labeled MN-14, the pretargeting strategy revealed much higher tumor-to-blood ratios due to the rapid clearance of the radiolabel from the circulation as compared with (111)In-MN-14 (445 +/- 90 and 5.3 +/- 1.1, respectively, at 72 hours postinjection).


CONCLUSIONS
Effective targeting of carcinoembryonic antigen-expressing tumors was achieved with a newly produced bispecific antibody. The (111)In-labeled L-amino acid peptide and 125I-D-amino acid peptide were better retained in the tumor than the 99mTc- and 125I-L-amino acid peptide. Very high tumor-to-blood ratios were obtained due to rapid background clearance.
van Schaijk
Frank G
FG
Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. F.vanSchaijk@hetnet.nl
Oosterwijk
Egbert
E
Soede
Annemieke C
AC
Broekema
Matthias
M
Frielink
Cathelijne
C
McBride
William J
WJ
Goldenberg
David M
DM
Corstens
Frans H M
FH
Boerman
Otto C
OC
D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000737:chemistry; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis*; D002412:Cations; D045744:Cell Line, Tumor; D002852:Chromatography, Ion Exchange; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006825:Hybridomas / Q000378:metabolism; D007205:Indium Radioisotopes / Q000737:chemistry / Q000627:therapeutic use*; D007457:Iodine Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D015233:Models, Statistical; D009336:Necrosis; D004369:Pentetic Acid / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D016499:Radioimmunotherapy / Q000379:methods*; D011877:Radionuclide Imaging; D013667:Technetium / Q000737:chemistry; D013997:Time Factors; D014018:Tissue Distribution
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D002412:Cations; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D010455:Peptides; D013667:Technetium; D004369:Pentetic Acid