Modern trends in radioimmunotherapy of cancer: pretargeting strategies for the treatment of ovarian cancer.
A review of published data on some of the problems associated in treating cancer using radioimmunotherapy is presented. Potential improvements for this type of therapy using pretargeting strategies are discussed and preliminary results on a novel multistep regimen to treat human ovarian cancer are presented. A pretargeting strategy using a biotinylated, anti-CA125 monoclonal antibody (MAb) to attract biotinylated long-circulating liposomes to the surface of CA125-expressing ovarian cancer cells, was employed. Confocal laser scanning microscopy and fluorescent labels were used to establish the biodistribution patterns in NIH:OVCAR-3 (CA-125 positive) and SK-OV-3 (CA-125 negative) human ovarian cancer cells. Shedding kinetics of the pretargeted stage were measured using 125I labeled MAbs. No significant internalization of the MAb used in the pretargeting step was observed by 4 hrs. The antibody was gradually internalized starting at 6 hrs, and most of the labelled MAb was detected in cytoplasm by 24 hrs. Shedding and exocytosis of the antigen-MAb complex was not significant for up to 6-hours following administration of the iodinated MAb. Biotinylated liposomes were shown to specifically target the biotinylated MAb/streptavidin complex on the cell surface. We have demonstrated that by a three-step pretargeting approach, biotinylated liposomes can be specifically delivered to cells pretargeted with biotinylated MAb/SAv complex. The slow internalization and shedding properties of the two MAbs are ideal for multistep pretargeting methods. A successful multistep linkage was established with the biotinylated MAb B27.1, streptavidin and biotinylated liposomes to OVCAR-3 cells, but not to SK-OV-3 cells.
McQuarrie
S A
SA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. smcquarrie@pharmacy.ualberta.ca
Xiao
Z
Z
Miller
G G
GG
Mercer
J R
JR
Suresh
M R
MR
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D006801:Humans; D008081:Liposomes; D010051:Ovarian Neoplasms / Q000532:radiotherapy*; D016499:Radioimmunotherapy; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D008081:Liposomes; D016650:Fluorescein-5-isothiocyanate