Abstract
The recent commercial success of PSMA peptide-based radioactive therapies and diagnostics (theranostics) has sparked increased interest in identifying peptide ligands for cancer targets. Phage display provides a high throughput screening platform for identifying novel peptide ligands for diverse proteins. In this study, we demonstrate the utility of screening large combinatorial libraries, totaling 1011 peptide sequences featuring linear, cyclic (one disulfide), and macrocyclic (two disulfides) peptides, against the Prostate Specific Membrane Antigen (PSMA) protein. The PSMA binding screens revealed five 12-amino acid peptides sharing the X2CX5CX2 motif and one sequence with the CX6CX4CXC motif that binds with high affinity. Next-generation sequencing (NGS) was also applied to the phage selection outputs, yielding >12,000 sequences and several families of peptides as potential binders. We further examined the ability of the PSMA-binding component of Pluvicto® Glu-Urea-Lys, which binds PMSA with an affinity of 13 nM, to block the binding of the discovered peptides. Pluvicto® did not displace either peptide family, indicating that the phage-derived ligands recognize a distinct binding site and could serve as starting points for a new class of PSMA-directed therapeutics. Overall, these findings highlight how high-throughput phage display can launch peptide-based therapeutic and diagnostic discovery efforts across many different targets.
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