The availability of the human genome sequence in the last decade has powered a new wave of protein therapeutics. Using a wide variety of bioinformatics technologies, it has been possible to identify a nearly complete list of all secreted proteins including important bio-therapeutic classes of cytokines, growth factors and hormones.
The challenge ahead is to identify the function of these secreted and cell surface proteins. A combination of classic low throughput and large scale industrialized biology approaches (functional genomics) promises to identify the roles of the newly discovered genes as well as to assign new roles for known proteins in both normal homeostasis and in the development and resolution of disease. Only a few proteins will be directly converted into protein therapeutics whereas others might become targets for monoclonal antibodies, the fastest growing segment of biotherapeutics.
Key to the success of therapeutics is the validation of the target in human disease(s). Recent advances in genotyping technologies now allow us to scan for genetic associations on a whole genome basis. This technology together with target validation approaches applying molecular biology, cell biology and pharmacology defines a new paradigm that will increase our confidence in progressing molecules towards the clinic.
As we learn more about the biological and therapeutic function of the first generation of protein therapeutics, new possibilities are emerging for second generations of modified proteins. Technologies are available that will increase the therapeutic efficacy of these parent products, by enhancing their potency and time of action, among other properties.
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Fig. 17.1. The pyramid of new therapies from the human genome. The top level, finding new therapeutic hormones, is the most difficult - since most hormones have already been identified based on cellular or physiological activity. The second level, finding new activities for existing proteins, is arguably more fruitful. Many proteins are pleiotropic, they have many activities, and often the initial discoverers focused only on one indication. The third level is that ofprotein engineering or antibody generation - where we tailor the biological activities to the needs in disease pathology, rather than physiology. The fourth level is that of replacing the proteins with small molecules or other technologies to improve the convenience for our patients. The increase in width of the pyramid as we descend describes the increase in the number ofpossible solutions to the problem
Proteins - natural or engineered - and antibodies along with small molecules form the pyramid of our therapeutic arsenal (Fig. 17.1).
Combining the access to the entire catalogue of secreted proteins with the ability to gain insights into the human disease through genetics, places us in a unique position to effectively find the protein therapeutic medicines of tomorrow.
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