The Use of Phage-Displayed Peptide Libraries to Develop Tumor-Targeting Drugs

Abstract

Monoclonal antibodies have been successfully utilized as cancer-targeting therapeutics and diagnostics, but the efficacies of these treatments are limited in part by the size of the molecules and non-specific uptake by the reticuloendothelial system. Peptides are much smaller molecules that can specifically target cancer cells and as such may alleviate complications with antibody therapy. Although many endogenous and exogenous peptides have been developed into clinical therapeutics, only a subset of these consists of cancer-targeting peptides. Combinatorial biological libraries such as bacteriophage-displayed peptide libraries are a resource of potential ligands for various cancer-related molecular targets. Target-binding peptides can be affinity selected from complex mixtures of billions of displayed peptides on phage and further enriched through the biopanning process. Various cancer-specific ligands have been isolated by in vitro, in vivo, and ex vivo screening methods. As several peptides derived from phage-displayed peptide library screenings have been developed into therapeutics in current clinical trials, which validates peptide-targeting potential, the use of phage display to identify cancer-targeting therapeutics should be further exploited.

Fig. 1.

Affinity selection (biopanning) process employed in phage-displayed peptide library screenings. The naïve peptide library is incubated with the target, washed to remove non-specific binding phage, and eluted to collect binding phage. The eluted phage are then amplified in vivo and subjected to additional rounds of biopanning, or can be plated to isolate clones for sequencing.

Fig. 2.

(a) Structure of a typical filamentous phage virion, and (b) a T7 lytic phage virion.

Fig. 3.

Differing processes of filamentous phage and lytic phage morphogenesis. (a) Filamentous phage assembles at the E. coli inner-membrane (IM) and is secreted through the outer-membrane (OM) into the extracellular environment, a process that preserves host viability. (b) Lytic phage assembles within the E. coli cytoplasm, and mature virions are released by cell lysis.