RADIOPHARMACOLOGY 

The Quarterly Journal of Nuclear Medicine 2001 June;45(2):160-6

Copyright © 2009 EDIZIONI MINERVA MEDICA

language: English

Modern trends in radioimmunotherapy of cancer: pretargeting strategies for the treatment of ovarian cancer

McQuarrie S. A., Xiao Z., Miller G. G., Mercer J. R., Suresh M. R.

From the Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta, Edmonton *Noujaim Institute for Pharmaceutical Oncology Research, University of Alberta, Edmonton, Canada

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.