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PEGylation of Therapeutic Proteins Development and Challange .pdf


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PEGylation of Therapeutic Proteins: Development
and Challange
The use of proteins as therapeutic agents has a long history and is becoming
increasingly common in modern medicine. Beginning with the use of
recombinant insulin in 1982, protein-based therapies have become an
important tool for combating diseases and illnesses. The United States Food
and Drug Administration (FDA) has approved more than 239
therapeutic proteins and peptides for clinical use. Due to the large size and
specific conformation of the protein, it has a highly specific binding and/or
activity advantage. This means that cross-reactions are less likely to cause
potentially fatal side effects. In addition, since most protein therapeutics are
based on endogenously expressed proteins, there is less chance of an
immunogenic reaction to them. In addition, due to the vast diversity of proteins,
they can be used to treat a variety of diseases: from treating endocrine
disorders, to fighting various cancers, to alleviating autoimmune diseases, to
being an active agent for many vaccines. This diversity makes proteins an
attractive option for researchers to develop new therapies.

However, the use of protein-based therapies is not without its challenges-one
of the disadvantages is that their half-life in the body may be short and
therefore require frequent dosing, which in turn increases the chance of
immunological response and increases the cost of treatment. Another potential
disadvantage of some protein therapeutics is that there may be dose-limiting
solubility issues, which may prevent proteins from being used as therapeutic
drugs. One of the main strategies to alleviate these problems is to attach
a polyethylene glycol (PEG) group to the target protein. This process,
calledPEGylation, has evolved tremendously in recent years, resulting in
several approved drugs. The application of PEGylation can be extended to

peptides, enzymes, antibody fragments, nucleotides, and even small organic
molecules.

protein PEGylation

Protein PEGylation Advantages
Protein PEGylation prolongs the cycle time of the protein because the
PEG-protein conjugation results in an increase in solution size and reduces the
kidney clearance time of the conjugate compared to unmodified
proteins. PEG has been approved by the US Food and Drug Administration
(FDA) as " generally recognized as safe". It is a flexible, randomly coiled
macromolecule that exhibits an extended conformation in water, which is
maintained when one terminus of PEG is conjugated to a protein. Linear PEG
is derived from ethylene oxide repeating units (HO- (CH2CH2O) n-H). PEG is
usually activated at one end for protein conjugation with a non-reactive methyl
group at the other end. The molecular weight of PEG for protein conjugation is
well dissolved in water under physiological conditions.

Currently, more than 17 different PEGylated drugs have been approved by the
FDA, and more potential products are under development. Although the total
number of PEGylated drugs is small compared to the total number of
protein-based therapeutics on the market, many of these PEGylated drugs are
still considered "blockbuster drugs." Overall, this indicates a great potential for
growth in commercial PEGylated therapeutics.

Protein PEGylation Disadvantages
The main disadvantage of PEGylation is usually reduced biological activity in
vitro, which can be compensated in vivo by significantly improved PK behavior.
Generally, the longer the PEG chain, the longer the elimination half-life of the
PEG-protein conjugate. Moreover, the polydispersity of the polymer is one of
the factors that aggravate the final characterization of the PEG-protein
conjugate. Current practice uses linear and branched-chain PEGs with
molecular weights up to 40 kDa, resulting in the desired improvement of PK
properties. However, new PEG formats (such as forked, multi-arm, and
comb-shaped PEGs) show great promise for the future. The macromolecular
structure of the conjugated PEG polymer appears to be critical for the
improved performance of the conjugate. In this sense, comb-shaped PEG with
many short PEG chains attached to the polymer backbone can be prepared
through transition metal-mediated living radical polymerization, providing a
relatively tightly controlled molecular weight and architecture of the polymer.
One promising approach is releasable PEGylation - attachment of a PEG

reagent with a releasable linker to a protein. This overcomes drug inactivation
by conjugation and enables the release of the full-potency drug, increases the
solubility of poorly soluble drugs and deposits such drugs at the target, allows
random PEGylation, and by appropriate selection of the linker also control of
PK parameters.

PEG reagents are commercially available in different lengths, shapes and
chemistries, allowing them to react with particular functional groups of proteins
for their covalent attachment. Biochempeg provides a variety of PEG product,
or activated PEG derivatives, that are crucial ingredients in the art of
PEGylation. The GMP manufacturing facility for the manufacturing of PEG
products is under construction and will be in operation this year.

Nearly five decades of development in PEGylation technology has proven its
pharmacological advantages and acceptability but the technology still lags in
providing a commercially attractive, generic process to produce highly specific
PEGylated therapeutic products at high yield. As a multi-million dollar annual
business with the growing interest from both emerging biotechnology and
established multinational pharmaceutical companies, there is great scientific
and commercial interest in improving present methodologies and in introducing
innovative process variations.


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