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Transcript
PEGylation Adam Jones What is PEG? PEG is an acronym for Polyethylene glycol It is also known as: • Polyethylene oxide (PEO) • Polyoxyethylene (POE) It is a polymer of ethylene oxide, and different lengths of the polymer have different uses. For the purpose of this presentation we will stick to the name PEG, and limit our explanation to how it can be used to extend the half-life (t1 ) 2 of blood borne proteins. PEG is simply repeating units of ethylene glycol. The chain can be as long as required, even branched if necessary. What is PEGylation? Put simply, PEGylation is a process by which PEG is covalently bound to another molecule such as a protein or peptide. As clotting factors are proteins, they are suitable candidates for this process. Why PEGylation? PEGylation is very useful in extending the t1 of blood borne proteins 2 and molecules. This is achieved in a few ways: 1. Increasing the relative molecular mass (Mr) of the protein of interest. 2. Decreasing the susceptibility of the protein of interest to proteolysis. 3. Altering the overall charge of the protein of interest (proteins generally carry an overall negative charge) thereby altering their kinetics in receptor mediated processes responsible for the clearance of these proteins. So what..? Well, the average half-life of plasma derived clotting factors VIII & IX is circa 8-12 and 19 hours respectively. In the case of haemophilia A & B, it makes sense to enable the administered clotting factors to stay in the circulation for an extended period of time, thus providing enhanced cover, and, in the severe phenotype, keeping spontaneous bleeding at bay. It is therefore a logical progression to utilise PEGylation as a way of achieving this aim. Inevitably this will also lead to further positive outcomes, such as: 1. Keeping trough levels of clotting factors higher in patients for longer 2. Reducing the required frequency of prophylactic injections 3. As the half-life is extended, prophylactic and/or treatment doses need not be so high, thus reducing factor consumption per patient capita 4. This reduced consumption has the knock on effect of reducing cost to the haemophilia unit. This is not just in direct savings, but also in indirect savings such as a reduction in the requirement for surgical interventions, pain management, inpatient stays, and so on. What can we expect? Well, that’s an interesting question… There have been animal studies performed which have demonstrated the t1 to have been extended by 2 between 2 and 4 times. Impressed? Don’t get too excited just yet as there is still quite a way to go before it becomes a mainstream treatment (including clinical trials), but it is looking promising nonethe-less!