Development of anti-infectives using phage display: biological agents against bacteria, viruses, and parasites

Abstract

The vast majority of anti-infective therapeutics on the market or in development are small molecules; however, there is now a nascent pipeline of biological agents in development. Until recently, phage display technologies were used mainly to produce monoclonal antibodies (MAbs) targeted against cancer or inflammatory disease targets. Patent disputes impeded broad use of these methods and contributed to the dearth of candidates in the clinic during the 1990s. Today, however, phage display is recognized as a powerful tool for selecting novel peptides and antibodies that can bind to a wide range of antigens, ranging from whole cells to proteins and lipid targets. In this review, we highlight research that exploits phage display technology as a means of discovering novel therapeutics against infectious diseases, with a focus on antimicrobial peptides and antibodies in clinical or preclinical development. We discuss the different strategies and methods used to derive, select, and develop anti-infectives from phage display libraries and then highlight case studies of drug candidates in the process of development and commercialization. Advances in screening, manufacturing, and humanization technologies now mean that phage display can make a significant contribution in the fight against clinically important pathogens.

Fig 1

Life cycle of filamentous phages. Filamentous phage binds to the F pilus of a host E. coli cell through pIII. Then the host TolA protein starts to depolymerize the phage coat proteins, which remain in the inner membrane for recycling. The ssDNA of the phage enters into the cytoplasm, converts into double-stranded DNA (dsDNA), and starts replication and expression using host enzymes. ssDNA and coated pV protein dimers form the precursors of the phage. Then pV is replaced by pVIII in the channel formed by pI, pXI, pIV, and host thioredoxin; in the meantime, mature phage particles are assembled and released.

Fig 2

Library construction systems. Black boxes indicate the gene fragments encoding pIII. Yellow boxes represent the foreign gene inserted into the pIII gene. Yellow circles show the fusion proteins expressed on the N terminus of the pIII protein.

Fig 3

Biopanning of a phage display library to select phage binding to an immobilized target.