276. Evaluation of an Oncolytic Adenovirus: Efficacy Studies on Primary Human Tumor Cell Cultures and Safety Studies in Non-Human Primates

Abstract

There is a great need for agents that target therapeutic agents, such as viral vectors, to prostate cancer cells. We have used phage display to identify short disulfide-constrained heptapeptides that bind specifically to the extracellular-portion of the Prostate Specific Membrane Antigen (PSMA), a type II integral membrane protein over-expressed on the surface of prostate cancer cells. Two separate phage display peptide strategies were applied, in parallel, to purified PSMA protein bound to two separate substrates. We reasoned that peptide sequences common to both substrate selections would be specific binders of PSMA. Additionally, the design allowed for stringent cross selections, where phage populations from one selection condition could be applied to the alternative substrate. These strategies resulted in a series of phage displayed peptides able to bind to PSMA by ELISA and direct binding assays, both with purified protein and in prostate cancer cells. PSMA specific cell binding is competitively inhibited by soluble, purified PSMA. The synthesized peptides are capable of binding PSMA protein and enhancing its carboxypeptidase enzymatic activity, suggesting protein folding stabilization. The discovery of these peptides provides the foundation for subsequent development of peptide targeted therapeutics against prostate cancer.