Improved Tumor Rediotherapy by MORF Pretargeting

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Pretargeting of tumor is becoming a mature, reasonably well understood and successful imaging modality. The advantage of pretargeting is usually not in higher absolute tumor accumulation but in higher tumor/normal tissue ratios achieved rapidly. This laboratory is exploring several novel approaches to pretargeting, each having in common the use of oligomers in place of either streptavidin/biotin or bispecific antibodies. In the course of investigating oligomers for "conventional" pretargeting, it became apparent that these interesting molecules have many useful properties for this application. In addition to conventional pretargeting, these studies have led to the development of three new subfields of investigation that we call "amplification pretargeting", "affinity enhancement pretargeting with oligomers" and,most recently, "optical pretargeting". Because of the novelty of using oligomers in radiopharmaceutical design, and in particular MORFs for pretargeting applications, we were required to develop methods of labeling MORFs with 99mTc and 188Re, develop new methods of conjugating antibodies and polymers with MORFs, develop methods of synthesizing bivalent MORFs with different spacings and,most recently, explore cellular accumulations of fluorophore conjugated MORFs. In addition, it was necessary to calibrate our tumor mouse model to better understand its properties with respect to pretargeting so that tumor and normal tissue accumulations could be accurately predicted with changes in variables. These and other developments have been successfully accomplished as documented in our publications in print, in press, submitted and in preparation. We intend to continue these investigations of MORF pretargeting by emphasizing our conventional preclinical pretargeting radiotherapy studies with 188Re-MORFs into (with supplemental funding) tracer studies in patients; 2) improving upon pretargeting by continuing our MORF amplification and MORF affinity enhancement pretargeting of tumors. We will also continue our MORF pretargeting studies with optical detection. Our multidisciplinary UMMS team consisting of chemists, radiation physicists and a molecular biologist has experience in each phase of this investigation. The proposed studies will now build upon our past results to achieve our goal of greatly improving upon conventional molecular targeting of tumor for improved cancer diagnosis and,especially, radiotherapy.