This project will examine the potential for improving radioimmunotherapy of pancreatic cancer using a bispecific antibody (bsMAb) pretargeting approach. We have previously shown very exciting data that pancreatic cancer specific anti-MUC1 MAb, PAM4, when radiolabeled with 90Y and combined with gemcitabine significantly enhanced the therapeutic effects of a gemcitabine regimen modeled after a human equivalent dosing regimen. We suspect that because pretargeting approaches can deliver similar amounts of radioactivity to tumors, but with less myelosuppression, that this type of procedure for targeting radionuclides would be preferred for eventual clinical use with gemcitabine. Therefore, one of the goals of this work will be to develop and test a bsMAb pretargeting procedure using PAM4 bsMAb with a 90Y or 177Lu- labeled peptide. AIM 1 includes studies designed to determine optimal targeting conditions for chemically conjugate F(ab')2 x Fab' or Fab' x Fab' PAM4 bsMAb. The optimal pretargeting conditions will be based on biodistribution and autoradiographic methods. Once optimized, the pretargeting procedures will be assessed for their therapeutic potential in the CaPanl cell line grown subcutaneously and orthotopically. Comparisons will be made between 90Y- and 177Lu as pretargeted agents, as well as to the directly radiolabeled PAM4 IgG. Repeat and fractionated doses will be examined. Combinational therapies will be tested using pretargeting added to a standard gemcitabine regimen, as well as assessing whether EGFR-based therapies (i.e., cetuximab and erlotinib) can further enhance this combination. Overall, these studies will assist in establishing whether this type of pretargeting approach could have a role in the clinical management of pancreatic cancer. [unreadable] [unreadable] [unreadable]