Two-step targeting of xenografted colon carcinoma using a bispecific antibody and 188Re-labeled bivalent hapten: biodistribution and dosimetry studies.
Radioimmunotherapy (RIT) is currently being considered for the treatment of solid tumors. Although results have been encouraging for pretargeted 131I RIT with the affinity enhancement system (AES), the radionuclide used is not optimal because of its long half-life, strong gamma emission, poor specific activity, and low beta particle energy. 188Re, though unsuitable for direct antibody labeling, could be used with the AES two-step targeting technique. The purpose of this study was to compare the distribution and dosimetry of a bivalent hapten labeled with 188Re or 125I. For dosimetry calculations and biodistribution data, 125I was substituted for 131I.


METHODS
After preliminary injection of a bispecific anticarcinoembryonic antigen (CEA) or antihapten antibody (Bs-mAb F6-679), AG 8.1 or AG 8.0 hapten radiolabeled with 188Re or 125I was injected into a nude mouse model grafted subcutaneously with a human colon carcinoma cell line (LS-174-T) expressing CEA. A dosimetry study was performed for each animal from the concentration of radioactivity in tumor and different tissues.


RESULTS
Radiolabeling of AG 8.1 with 125I afforded a 40% yield with a specific activity of 11.1 MBq/nmol after purification. Radiolabeling of AG 8.0 with 188Re afforded a 72% yield with a specific activity of 31.82 MBq/nmol. In all experiments, the percentage of tumor uptake of 125I-AG 8.1 was always significantly greater than that of 188Re-AG 8.0. The corresponding tumor-to-tissue ratios reflected uptake values. The least favorable tumor-to-normal tissue ratios in the dosimetry study were 8.1 and 8.5 for 131I (tumor-to-blood ratio and tumor-to-kidney ratio, respectively) and 2.3 for 188Re (tumor-to-intestine ratio).


CONCLUSIONS
This study indicates that 188Re can be used for radiolabeling of hapten in two-step radioimmunotherapy protocols with the AES technique. 188Re has a greater range than 131I, which should allow the treatment of solid tumors around 1 cm in diameter. Although the method used for hapten radiolabeling did not provide optimal tumor uptake, the use of a bifunctional chelating agent associated with AG 8.1 should solve this problem.
Gestin
J F
JF
Institut de Biologie, Institut National de la Santé et de la Recherche Médicale, Nantes, France.
Loussouarn
A
A
Bardiès
M
M
Gautherot
E
E
Gruaz-Guyon
A
A
Saï-Maurel
C
C
Barbet
J
J
Curtet
C
C
Chatal
J F
JF
Faivre-Chauvet
A
A
D000818:Animals; D003110:Colonic Neoplasms / Q000532:radiotherapy*; D006241:Haptens; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000627:therapeutic use*; D011874:Radiometry; D012211:Rhenium / Q000627:therapeutic use*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D006241:Haptens; D007457:Iodine Radioisotopes; D011868:Radioisotopes; D012211:Rhenium