Drug Targeting Organ-Specific Strategies

270 10 Phage Display Technology for Target Discovery in Drug Delivery Research
10.6 Conclusions
Phage display has become the most efficient and effective method developed to date for
rapidly identifying peptides, antibodies and other proteins that bind to molecular targets.
Some of these ligands have biological effector functions or are candidates for ligand-based
drug targeting. Identification of the antigens targeted by phage-displayed ligands has been
simplified by this technology, by the use of DNA display libraries and by coupling gene isolation
and clone identification with affinity selection, facilitating the search for novel targets
and biologically important antigens. Selection for function allows the retrieval of ligands with
effector functions for use in the generation of drugs. Selection for cellular internalization has
opened a new door for the delivery of macromolecular constructs and coupled drugs into the
cytoplasm of mammalian cells.
The physical bond between the selected ligand and its encoding gene allows further manipulation
of the ligands to obtain optimal affinity and avidity, size, and valency. Furthermore,
the coupling of a drug to the targeting ligands can be readily engineered.
The design features required for an optimally-effective drug and/or targeting agent can be
readily obtained by phage display technology. Many features give phage display technology
clear advantages over conventional approaches for the generation of reagents for drug targeting
purposes. These include diversity in protein type and sequence space of combinatorial
phage libraries, the power of filamentous phage-based selection, the possibilities of genetic
manipulation to generate more effective ligands and specific effector functions, and the
adaptability of the system for the production of therapeutic ligands derived from the libraries.
In the near future phage display technology may have further application in the rapid
analysis and comparison of protein profiles of large proteomes, such as human cells and tissue.Arrays
of phage-displayed proteins such as antibodies or peptides, which selectively bind
to proteins from a complex mixture can be generated. Proteins absorbed by the antibody arrays
can then be analysed by mass spectrometry. Such technologies will be especially useful
for identifying differences between cell or tissue samples such as healthy versus diseased
states, and may lead to the identification of drug targets. Once a protein of interest has been
identified, its corresponding antibody or peptide ligand can be retrieved and used to monitor
protein expression or modification in a range of cell or tissue samples, and can also be used
for cloning the target antigen.
Phage display has become a powerful method for the generation of protein-based binding
and biologically active reagents. In the forthcoming years an extensive application of this
technique is predicted for the development of drugs and drug targeting entities.
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