The overall goal of this program project is the translational development of radioisotopic carrier molecules and strategies to deliver systemic radiotherapy for lymphomas and adenocarcinomas such as prostate cancer. The first project focuses on developing novel synthetic high affinity ligands (SHALs) that will target the Lym-1 epitope of the beta subunit of HLA-DR, known to be present on malignant lymphocytes of almost all B cell types. The second project focuses on developing novel bispecific multivalent single chain variable fragment (scFv) MAbs to be used to pretarget prostate cancer and to be followed by a small multivalent DOTA chelator of 90y. Several different types of molecular modeling has been used in support of the Projects. Homology-based protein structure prediction was used to determine: 1) the structures of HLA-DR 10, and 2) scFv MAb targeting agents, as well as 3) the scFv raised against the 90y DOTA chelator. These predicted structures were used to help identify: 1) the Lym-1 MAb epitope for subsequent computational docking studies and 2) scFv binding sites against the DOTA chelator. Quantum chemical simulations and first principles molecular dynamics simulations were used to predict the effects of chemical modifications on the structure of the 90Y-DOTA and the DOTA-DOTA linker. Finally, classical molecular dynamics were used to assist in determining the binding orientations of ligands, the design of SHALS, the optimization of the DOTA-DOTA linker and PEGylated scFv scaffold. This core component provided the computational simulation expertise and facilities to achieve these aims. All simulations were performed using computer hardware and software already available to the group. We have significant computer resources within the biology program, and extensive computer time on much larger institutional computer facilities through internal grants. The investigators selected for this Core have extensive experience in the different molecular modeling methods to be employed.
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