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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!