Protein and ligand interactions drive multiple biological processes. Phage display allowed researchers the possibility to study and interfere with these interactions in a controlled environment leading to the development of countless applications. Today, the most successful applications of phage display rest on its use as an antibody discovery, engineering, and epitope mapping tool. Check our frequently asked questions (FAQs) page about phage display. for a complete overview of all steps of this robust process for antibody generation.
The phage display technology was created by scientist Georg Smith in the mid-1980s with the purpose of studying protein-ligand interactions. The technique was first applied to small peptide display and later optimized for the study of larger molecules like antibodies.
In its essence, phage display is a screening methodology adapted both to liquid-phase and semi-solid phase environments against solubilized or immobilized ligands, respectively. Since phenotype is linked to genotype in phage display, the technology can be used to quickly build, amplify, and screen vast libraries of proteins (up to 1010 different clones).
Because protein/ligand interactions are essential to every biological system, the applications of phage display are numerous. But on a general level, phage display is mostly used to isolate proteins with novel or improved properties, select peptides to functionalize other molecules, or generate whole phage particles to be used directly in applications such as biosensors (e.g. for pathogen or toxin detection).
With the advent of molecular biology techniques, the antibody repertoire of countless host species became accessible to scientists. Following protocols of mRNA isolation, cDNA synthesis, and antibody gene amplification (VL, VH, and VHH), massive antibody repertoires could be built in vitro in very short timeframes. But only after the boom of display technologies, did the exploitation of these repertoires became feasible.
The most important applications of antibody phage display include:
The most conventional application of antibody phage display is the field of lead discovery. Drawing from the high diversity of naïve antibody repertoires or from the high selectivity of their immune counterparts, phage display achieves the enrichment of binders with novel properties and high affinity towards a specific antigen.
The unique strengths of antibody phage display in comparison to in vivo methods of antibody discovery (i.e. hybridoma, transgenic mice, etc.) include:
In general, phage display applications extend the boundaries imposed by more conventional antibody discovery techniques like hybridomas. Hybridoma development is a time-consuming technique and the hybrid cell lines themselves can often be rather unstable.
On the contrary, phage display can be used to eliminate the need to immunize animal hosts (naïve libraries) or to perform antibody sequencing, since the sequences can be easily obtained by amplifying antibody-encoding genes from the most promising phages.
In recent years, scientists have continued optimizing the use of phage display for alternative applications. One of the most successful of these recent applications has been the use of this technology for antibody engineering.
Affinity maturation by phage display is a well-established antibody engineering approach. It allows researchers the possibility to screen large and complex antibody mutant libraries to increase the affinity, stability, and developability of weak antibodies. However, recently some scientists have been taking this one step further by engineering biospecific antibodies.
Since phage display is driven by the principle of protein-ligand interactions, scientists have begun applying it to improve bispecific antibody assembly in vitro. Bispecific antibodies have been considered for many years as extremely challenging to produce. Because the two sets of antibody chains (VH and VL) need to be expressed and assembled in the same organism, production batches consist of mixtures of bispecific and misassembled variants.
To guide the assembly of these antibodies, scientists have ingeniously been using phage display to increase the affinity of VH and VL chains towards each other. By using this approach, it is possible to ensure that the bispecific variant with the proper VH/VL pairing is favored during expression in recombinant systems.
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