Improved Tumor Radiotherapy by MORF pretargeting

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Despite several decades of effort, conventional radioimmunotherapy of hematopoietic and especially solid tumors is still providing marginal results. As such, alternative methods of treating these diseases are needed. Arguably one of the most attractive alternative approaches involves pretargeting. Preclinical studies of pretargeting have clearly demonstrated efficacy and early clinical trials are providing encouraging results. These studies usually involve biotin and (strept)avidin. Unfortunately (strept)avidin has been found to be immunogenic and endogenous biotin has been shown to interfere. Another approach, involving bispecific antibodies, replace these difficulties with difficulties in antibody and hapten preparation. Bispecific antibodies also show orders-of-magnitude lower affinities - an important consideration for pretargeting. Investigators at UMMS have been exploring 99mTc-labeled oligonucleotides, one DNA chemical analogue: peptide nucleic acid (PNA) and, most recently, another DNA chemical analogue: morpholinos (MORF) for this application and have shown in preliminary studies that pretargeting with MORFs may potentially solve the above difficulties. We have shown by surface plasmon resonance that the association rate constant of a 18-mer MORF for its MORF complement (cMORF) is equivalent of that of DNAs of comparable lengths and therefor equivalent to that of biotin for (strept)avidin. We have also found that radiolabeled MORFs show rapid clearance kinetics in mice almost exclusively through the kidneys. Furthermore, there is, of course, no endogenous MORF problem. Excellent results have already been obtained with 99mTc-MAG3-MORF administered to LS174T tumor bearing nude mice following the administration of MN-14-cMORF. This study will establish the optimum conditions of dosage and timing for pretargeted localization of 99mTc in tumored mice. These conditions will then be reproduced using MORF labeled with 188Re to investigate the therapeutic potential of this approach, again in tumored mice. This collaborative investigation brings together researchers from Gene Tools and their knowledge of MORF, from Immunomedics and Garden State Cancer Center with their expertise in therapeutic pretargeting and from UMMS who have experience in the radiolabeling and in vivo uses of MORFs and other oligomers. We are confident that these investigations will confirm that pretargeting with MORF can significantly improve upon the therapy now achievable with conventional radioimmunotherapy and may be superior to pretargeting approaches involving biotin/(strept)avidin or bifspecific antibodies.