Biomedical Engineering Reference
In-Depth Information
the drug onto PEG, multi-arm PEG (a four-armed-PEG derivative) was used to
enable the conjugation of four drugs to one molecule [
52
]. This conjugate will now
be assessed in further preclinical development and clinical trials [
53
].
4.2 Peptides, Proteins, Antibodies, and Antibody Fragments
The majority of approved PEGylated drugs are categorized into this group. Eight
PEGylated proteins, including antibody fragment conjugates, have been approved
to date. Adagen is the first approved PEGylated product in which bovine adenosine
deaminase is randomly conjugated with a 5-kDa mono-methoxy PEG [
54
]. This
conjugate is synthesized using PEG succinimidyl succinate. This activated ester
group can be reacted with nucleophilic amino acid units such as lysine. Since the
approval of Adagen, seven other protein-PEG conjugates have been approved.
Although nonspecific PEGylation has been reported to decrease the activity of
protein in some cases, several approved drugs employ nonspecific PEGylation.
Krystexxa, which was approved in 2010 for the management of treatment-resistant
gout and hyperuricemia, was also prepared using nonspecific PEGylation. A conju-
gate containing six strands of 10-kDa PEG per subunit was found to have a
significantly longer half-life in blood and dramatic urate-lowering potency [
55
].
In contrast to nonspecific PEGylation, several protein-PEG conjugates have
adopted site-specific PEGylation. Cimzia is a PEGylated anti-tumor necrosis factor
(TNF)-
a
antibody fragment used for the treatment of Crohn's disease and rheuma-
toid arthritis [
27
]. Recent progress in biotechnology has enabled low-cost produc-
tion of the recombinant antibody fragment by
Escherichia coli
expression [
56
].
However, such proteins, which are obtained and purified from
E. coli,
often possess
immunogenicity. PEGylation on the protein reduces the immunogenicity of the
recombinant non-human protein. To prepare Cimzia, the C-terminal cysteine is
reacted with maleimide, which is introduced at the end of the 40-kDa branched PEG
chain [
27
].
Another type of PEG-antibody fragment is PEGylated di-Fab, in which two
antibody fragments are attached to PEG [
57
]. CDP791 is prepared using a bis-
maleimide PEG and a humanized antibody fragment, resulting in a divalent
PEGylated Fab fragment. This unique architecture enables high affinity for vascular
endothelial growth factor receptor 2 (VEGFR-2), resulting in reduction of solid
tumors [
58
].
4.3 Oligonucleotide-PEG Conjugates
Oligonucleotide-based drugs such as antisense drugs, aptamers, and small
interfering RNA (siRNA) have attracted considerable attention as promising thera-
peutic agents for the treatment of various human diseases [
59
]. To develop