Biodistribution and therapeutic efficacy of (125/131)I-, (186)Re-, (88/90)Y-, or (177)Lu-labeled monoclonal antibody MN-14 to carcinoembryonic antigen in mice with small peritoneal metastases of colorectal origin.
Therapeutic efficacy in radioimmunotherapy depends, among other things, on the choice of the radionuclide. The aim of the present study was to determine the most suitable radionuclide for radioimmunotherapy with monoclonal antibody MN-14 to carcinoembryonic antigen in an experimental model of small peritoneal metastases of colorectal origin.


METHODS
In nude mice with intraperitoneal LS174T tumors (diameter, 1-3 mm), the biodistributions of MN-14 labeled with (131)I ((131)I-MN-14), (186)Re-mercaptoacetyltriglycine ((186)Re-MN-14), and (88)Y-diethylenetriaminepentaacetic acid (DTPA) ((88)Y-MN-14) after intravenous and intraperitoneal administration were determined. Subsequently, the therapeutic efficacies of equally toxic activity doses of (131)I-MN-14 (9.25 MBq per mouse), (186)Re-MN-14 (9.25 MBq per mouse), (90)Y-MN-14 (3.15 MBq per mouse), and MN-14 labeled with (177)Lu-DTPA ((177)Lu-MN-14) (8.33 MBq per mouse) after intraperitoneal administration were determined.


RESULTS
Each of the radioimmunoconjugates preferentially accumulated in tumor nodules, both after intravenous administration and after intraperitoneal administration. Values for clearance from blood were similar for all radioimmunoconjugates. The uptake of (88)Y-MN-14 in the liver and spleen was significantly higher than the uptake of (131)I-MN-14 or (186)Re-MN-14. Maximal uptake values (mean +/- SD) in tumors were 58 +/- 7 percentage injected dose per gram of tissue (%ID/g) for (131)I-MN-14 (24 h after administration), 83 +/- 19 %ID/g for (186)Re-MN-14 (72 h after administration), and 148 +/- 89 %ID/g for (88)Y-MN-14 (192 h after administration). Dosimetric analysis of the biodistribution data estimated that the radiation doses guided to the tumor by intraperitoneally administered (131)I-MN-14, (186)Re-MN-14, (90)Y-MN-14, and (177)Lu-MN-14 were 150, 100, 45, and 200 Gy, respectively. The median survival time of control mice, treated with unlabeled MN-14, was 42 d, whereas the median survival times of mice treated with (131)I-MN-14, (186)Re-MN-14, (90)Y-MN-14, and (177)Lu-MN-14 were 100 d (range, 58-142; P < 0.0001), 72 d (range, 46-84; P = 0.0002), 82 d (range, 46-142; P < 0.0001), and 136 d (range, 56-142; P < 0.0001), respectively. At the completion of the experiment (142 d after tumor cell inoculation), no residual disease was found in 8 of 9 long-term survivors ((131)I, n = 3; (90)Y, n = 1; and (177)Lu, n = 4).


CONCLUSIONS
The uptake of (88)Y-MN-14 in small peritoneal LS174T xenografts was higher than the uptake of (131)I-MN-14 or (186)Re-MN-14. The present study indicates that (131)I and (177)Lu are the most suitable radionuclides for the radioimmunotherapy of small peritoneal metastases.
Koppe
Manuel J
MJ
Department of Surgery, University Medical Center Nijmegen, Nijmegen, The Netherlands. m.koppe@chir.umcn.nl
Bleichrodt
Robert P
RP
Soede
Annemieke C
AC
Verhofstad
Albert A
AA
Goldenberg
David M
DM
Oyen
Wim J G
WJ
Boerman
Otto C
OC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008187:Lutetium / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009928:Organ Specificity; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000532:radiotherapy* / Q000556:secondary; D016499:Radioimmunotherapy / Q000379:methods; D011868:Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D015203:Reproducibility of Results; D012211:Rhenium / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D008187:Lutetium; D012211:Rhenium