Amplification targeting: a modified pretargeting approach with potential for signal amplification-proof of a concept
Department of Radiology
Animals; Cell Line, Tumor; Colonic Neoplasms; Drug Delivery Systems; Feasibility Studies; Gene Targeting; Humans; Indium Radioisotopes; use; Isotope Labeling; Metabolic Clearance Rate; Mice; Mice, Nude; Nucleic Acid Amplification Techniques; Oligonucleotides; Organ Specificity; Radiopharmaceuticals; use; Technetium; use; Tissue Distribution; Tumor Markers, Biological
Life Sciences | Medicine and Health Sciences
Conventional nuclear medicine imaging with large radiolabeled molecules such as antitumor antibodies suffers from slow localization and clearance. Pretargeting is under active investigation as an alternative using either (strept)avidin/biotin, bispecific antibodies, or oligomers. However, only the use of oligomers such as phosphorodiamidate morpholinos (MORFs) in pretargeting offers the potential of signal amplification at the target. Amplification targeting is a multistep procedure with the potential to greatly improve target localization of radioactivity (and eventually drugs) through the intermediate use of polymers conjugated with multiple copies of oligomers. OBJECTIVE: This study was conducted to prove the concept in vivo in tumored mice of amplfication targeting. METHODS: Nude mice bearing LS174T tumors received in order: the anti-CEA antibody MN14 conjugated with MORF, a polymer conjugated with multiple copies of complementary MORFs (cMORFs), and, finally, (99m)Tc-MORF. RESULTS: In tumored animals, dual radiolabels ((99m)Tc and (111)In) were used to demonstrate that, after 18 h, about 25% of antibody MORFs in tumor were targeted with polymeric cMORFs and, after 3 h, about 12% of the polymeric cMORFs in tumor were targeted with (99m)Tc-MORF. Therefore, hybridization in tumor in both cases (i.e., polymeric cMORF to antibody MORF and radiolabeled MORF to polymeric cMORF) was surprisingly efficient given the barriers to targeting in vivo and the competition between targeting and clearance. Moles of radiolabeled MORF accumulating in tumor were more than tripled for study animals receiving all 3 injections compared with control animals not receiving the antibody or the polymer. Furthermore, MORF expression (on antibody) and cMORF expression (on polymer) were rapidly lost in normal organs such as liver, spleen, and kidneys but not in tumor, thus improving the target-to-nontarget ratios. CONCLUSION: Although signal amplification has not yet been convincingly demonstrated and amplification targeting will require further studies for optimization, the concept has now been shown to be feasible.
J Nucl Med. 2004 Jun;45(6):1087-95.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
He J, Liu G, Gupta S, Zhang Y, Rusckowski M, Hnatowich DJ. (2004). Amplification targeting: a modified pretargeting approach with potential for signal amplification-proof of a concept. Open Access Publications by UMMS Authors. Retrieved from https://escholarship.umassmed.edu/oapubs/1187