Since then, PEGylation has been frequently used to modify proteins, peptides, oligonucleotides, antibody fragments, organic small molecules and nanoparticles. In the wave of novel coronavirus vaccine development, PEG was first and successfully applied to vaccines. Both BioNTech's and Moderna's mRNA vaccines have an active ingredient structure consisting of lipid nanoparticles encapsulating viral mRNA sequences, which include PEG-2000. PEG-2000 can increase the efficiency of transporting the mRNA to the cell, effectively improving its stability and half-life. By 2023, the FDA has approved more than 40 PEGylated drugs.

1. Huateng Pharma https://us.huatengsci.com/
1
List of FDA Approved PEGylated Drugs Up to 2023
Polyethylene glycols (PEGs) are non-toxic, non-immunogenic, non-antigenic, highly soluble in water,
and FDA approved. PEGylation is the chemical modification process of attaching a PEG active derivative to a
therapeutic protein/peptide drug or drug delivery system (e.g., nanoparticles, nucleic acid drug delivery
platforms, etc.).
Figure 1. PEGylation process
PEGylation alters the physical and chemical properties of biomedical molecules, such as conformation,
electrostatic binding, and hydrophobicity, thereby improving the pharmacokinetic behavior of drugs. In general,
PEGylation improves drug solubility and reduces immunogenicity. PEGylation also increases drug stability and
retention time in the bloodstream, reduces proteolysis and renal excretion, thereby allowing a reduced dosing
frequency. To benefit from these favorable pharmacokinetic outcomes, a variety of therapeutic proteins,
peptides, antibody fragments, and small molecule drugs have been PEGylated.
Figure 2. Advantages of PEGylation

2. Huateng Pharma https://us.huatengsci.com/
2
History of PEGylation
In the 1970s, Professor Frank Davis of Rutgers University modified bovine serum albumin with PEG in order to
reduce the immunogenicity of recombinant proteins, extend their in vivo metabolism time, and enhance protein
activity, and since then, this technology has been widely used in biomedical and other fields.
PEGylated drugs were clinically and commercially available in the 1980s. In 1981, Prof. Davis founded Enzon, Inc.
in the USA, and in 1990, the world's first PEGylated drug, Adagen (pegademase bovine) was approved by the
FDA for enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe
combined immunodeficiency disease (SCID).
Since then, PEGylation has been frequently used to modify proteins, peptides, oligonucleotides, antibody
fragments, organic small molecules and nanoparticles. In the wave of novel coronavirus vaccine development,
PEG was first and successfully applied to vaccines. Both BioNTech's and Moderna's mRNA vaccines have an
active ingredient structure consisting of lipid nanoparticles encapsulating viral mRNA sequences, which include
PEG-2000. PEG-2000 can increase the efficiency of transporting the mRNA to the cell, effectively improving its
stability and half-life. By 2023, the FDA has approved more than 40 PEGylated drugs.
Trade name [generic
name]
Approval holder Parent drug
PEG
size
(kDa)
Mode of action of
PEG
PEG
topology
Indication Year
Proteins
Izervay
(avacincaptad pegol)
Iveric Bio
Ribonucleic
acid aptamer
43
Increase in
circulating
half-life
Branched
Geographic
atrophy secondary
to AMD
2023
Elfabrio®
[Pegunigalsidase
alfa-iwx]
Chiesi
Farmaceutici
S.p.A
Human
α-galactosida
se-A
2.3
Enzyme stability
enhancement
Linear
(dual-functi
onal)
Fabry disease 2023
Fylnetra™
[Pegfilgrastim-pbbk]
Amneal
Pharmaceuticals
LLC
G-CSF 20
Increase in
circulating
half-life
Linear
Infection during
chemotherapy
2022
Stimufend®
[Pegfilgrastim-fpgk]
Fresenius Kabi G-CSF 20
Increase in
circulating
half-life
Linear
Infection during
chemotherapy
2022
Rolvedon™
[Eflapegrastim-xnst]
Spectrum
Pharmaceuticals
G-CSF 3.4
Linkage between
G-CSF and an Fc
fragment of
immunoglobulin
G4
Linear
(dual-functi
onal)
Infection during
chemotherapy
2022
Skytrofa™
[Lonapegsomatropin
-tcgd]
Ascendis
Human
growth
hormone
40
Increase in
circulating
half-life
Branched
(4 arms)
Growth hormone
deficiency
2021
Besremi™
[Ropeginterferon
alfa-2b-njft]
PharmaEssentia
Corp
Interferon-α-
2b
40
Increase in
circulating
half-life
Branched
(2 arms)
Polycythemia vera 2021

3. Huateng Pharma https://us.huatengsci.com/
3
Nyvepria™
[Pegfilgrastim-apgf]
Pfizer, Inc. G-CSF 20
Increase in
circulating
half-life
Linear
Infection during
chemotherapy
2020
Esperoct®
[Turoctocog alfa
pegol]
Novo Nordisk
Coagulation
Factor VIII
40
Increase in
circulating
half-life
Branched
(2 arms)
Hemophilia A 2019
Ziextenzo™
[Pegfilgrastim-bmez]
Sandoz G-CSF 20
Increase in
circulating
half-life
Linear
Infection during
chemotherapy
2019
Jivi™ [Damoctocog
alfa pegol]
Bayer
Healthcare
Coagulation
Factor VIII
(B-domain
deleted)
60
Increase in
circulating
half-life
Branched
(2 arms)
Hemophilia A 2018
Palynziq™
[Pegvaliase-pqpz]
BioMarin
Pharmaceutical
Phenylalanin
e
ammonia-lya
se
20
Reduction in
immune
recognition
Linear Phenylketonuria 2018
Revcovi™
[Elapegademase-lvlr]
Leadiant
Bioscience
Adenosine
deaminase
5.6
Reduction in
immune
recognition
Linear ADA-SCID 2018
Asparlas™
[Calaspargase
pegol-mknl]
Servier Pharma
L-asparaginas
e
5
Increase in
circulating
half-life and
reduction in
immune
recognition
Linear
Acute
lymphoblastic
leukemia
2018
Fulphila™
[Pegfilgrastim-jmdb]
Mylan GmbH G-CSF 20
Increase in
circulating
half-life
Linear
Infection during
chemotherapy
2018
Udenyca™
[Pegfilgrastim-cbqv]
Coherus
Biosciences
G-CSF 20
Increase in
circulating
half-life
Linear
Infection during
chemotherapy
2018
Rebinyn® [Nonacog
beta pegol]
Novo Nordisk
Coagulation
Factor lX
40
Increase in
circulating
half-life
Branched
(2 arms)
Hemophilia B 2017
Adynovate®
[Rurioctocog alfa
pegol]
Baxalta
Coagulation
Factor VIII
(ADVATE)
20
Increase in
circulating
half-life
Branched
(2 arms)
Hemophilia A 2015
Plegridy™
[Peginterferon
beta-1a]
Biogen
Interferon
β-1a
20
Increase in
circulating
half-life
Linear Multiple sclerosis 2014

4. Huateng Pharma https://us.huatengsci.com/
4
Sylatron™
[Peginterferon
alfa-2b]
Merck
Interferon-α-
2b
12
Increase in
circulating
half-life
Linear Melanoma 2011
Krystexxa®
[Pegloticase]
Horizon Pharma Urate oxidase 10
Reduction in
immunogenicity
Linear Chronic gout 2010
Cimzia™
[Certolizumab pegol]
UCB, Inc.
anti-TNFα
Fab'
40
Increase in
circulating
half-life
Branched
(2 arms)
Crohn's Disease,
Rheumatoid
arthritis, Psoriatic
arthritis,
Ankylosing
spondylitis
2008
Mircera™ [Methoxy
polyethylene
glycol-epoetin beta]
Roche
Erythropoieti
n
30
Increase in
circulating
half-life
Linear
Anemia associated
with chronic
kidney disease
2007
Somavert™
[Pegvisomant]
Pfizer
Human
growth
hormone
5
Increase in
circulating
half-life
Linear Acromegaly 2003
Neulasta®
[Pegfilgrastim]
Amgen G-CSF 20
Increase in
circulating
half-life
Linear
Infection during
chemotherapy
2002
Pegasys™
[Peginterferon
alfa-2a]
Roche
Interferon-α-
2a
40
Increase in
circulating
half-life
Branched
(2 arms)
Chronic hepatitis
C, Chronic
hepatitis B,
Cirrhosis and
compensated liver
disease, CHC/HIV
coinfection
2002
Pegintron™
[Peginterferon
alfa-2b]
Schering
Interferon-α-
2b
12
Increase in
circulating
half-life
Linear Chronic hepatitis C 2001
Oncaspar™
[Pegaspargase]
Enzon
L-asparaginas
e
5
Increase in
circulating
half-life and
reduction in
immune
recognition
Linear
Acute
lymphoblastic
leukemia
1994
Adagen™
[Pegademase
bovine]
Enzon
Adenosine
deaminase
5
Reduction in
immune
recognition
Linear ADA-SCID
1990/Disc
ontinued
Small molecules
Syfovre™
[Pegcetacoplan]
Apellis
Pharmaceuticals
, Inc.
Complement
C3 inhibitor
peptide
40
Increase in
circulating
half-life
Linear
(dual-functi
onal)
Geographic
atrophy secondary
to AMD
2023

5. Huateng Pharma https://us.huatengsci.com/
5
Empaveli™
[Pegcetacoplan]
Apellis
Pharmaceuticals
, Inc.
Complement
inhibitor
peptide
40
Increase in
circulating
half-life
Linear
(dual-functi
onal)
Paroxysmal
nocturnal
hemoglobinuria
2021
Movantik®
[Naloxegol]
AstraZeneca Naloxone 0.323
Reduced
permeability into
CNS
Linear
Opioid-induced
constipation
2014
Omontys™
[Peginesatide]
Takeda
Erythropoieti
n mimetic
peptide
40
Increase in
circulating
half-life
Branched
(2 arms)
Anemia due to
chronic kidney
disease
2012/Disc
ontinued
Macugen™
[Pegaptanib sodium]
Pfizer RNA aptamer 40
Increase in
intravitreal
residence time
Branched
(2 arms)
Neovascular (wet)
age-related
macular
degeneration
2004/Disc
ontinued
Nanoparticles
Spikevax® [COVID-19
Vaccine, mRNA]
Moderna
mRNA in
LNPs
2
Reduction in
protein
adsorption and
phagocytic
clearance
Linear (on
NPs)
COVID-19 2022
Comirnaty™
[COVID-19 Vaccine,
mRNA]
BioNTech/Pfizer
mRNA in
LNPs
2
Reduction in
protein
adsorption and
phagocytic
clearance
Linear (on
NPs)
COVID-19 2021
Onpattro® [Patisiran]
Alnylam
Pharmaceuticals
siRNA in LNPs 2
Reduction in
protein
adsorption and
phagocytic
clearance
Linear (on
NPs)
Polyneuropathy of
hereditary
transthyretin-medi
ated amyloidosis
2018
Onivyde™
[Irinotecan
liposome]
Merrimack
Pharmaceuticals
Irinotecan in
liposome
2
Reduction in
protein
adsorption and
phagocytic
clearance
Linear (on
NPs)
Metastatic
adenocarcinoma of
the pancreas post
gemcitabine
treatment
2015
Doxil® [Doxorubicin
HCl liposome]
Schering
Doxorubicin
in liposome
2
Reduction in
protein
adsorption and
phagocytic
clearance
Linear (on
NPs)
Ovarian cancer,
Multiple myeloma,
AIDS-related
Kaposi's Sarcoma
1995
Table1. FDA approved PEGylated drugs up to 2023 [1]
Advantages of PEGylated drugs
1. Significantly extends the half-life of protein peptide drugs in vivo

6. Huateng Pharma https://us.huatengsci.com/
6
Long-acting PEGylated protein/peptide drugs can be formed by synthesizing specific PEG derivatives and
combining their end groups with specific proteins and peptides. This class of drugs can be released slowly in the
body, which stabilizes the blood concentration and reduces drug dosing.
▶ Increases the relative molecular weight of the drug: the drug is less likely to be degraded and excreted by
renal filtration, prolonging the effective concentration of the drug in the body.
▶ Forms a barrier on the surface of the drug and delivery system: The long-chained PEG derivatives encapsulate
the drug, avoiding phagocytosis by the reticuloendothelial system, inhibiting proteolytic cleavage, and preventing
the drug from being rapidly enzymatically cleaved or recognized by the immune system.
2. Significantly improved solubility of small molecule drugs in vivo
Some small molecule drugs, although highly active, are often difficult to dissolve in water and have high toxicity,
making it difficult to be used as needles or injections for the human body, such as camptothecin, paclitaxel, etc.
As PEG derivatives have good water solubility, PEGylated small molecule drugs can be quickly dissolved in water
and then safely absorbed by the human body. Movantik™ was the first PEGylated small molecular drug approved
by the FDA in 2014 as an opioid antagonist, which carrys a PEG moiety with size of less than 1 kDa.
▶ Increases the hydrophilicity of the drug : Increases the solubility of small molecule drugs and decreases the
glomerular filtration rate;
▶ Increases the relative molecular weight of the drug : Small molecule drugs have a small relative molecular
weight and are very easily filtered out of the body by the human kidney. Small molecule drugs have a small
molecular weight and are easily excreted by the kidneys. Low concentrations of small molecule drugs in the
human body result in insignificant drug effects, while high concentrations of small molecule drugs cause strong
side effects in the human body. PEGylated small molecule drugs have increased relative molecular weights, and a
single injection can maintain the effective drug concentration in the body for a longer period of time, enabling
effective drug concentration to be maintained in the lesion continuously between drug administration, and
improving the safety of the drug.
3. Significantly enhance in vivo targeting of biologic drug delivery platforms (LNPs)
PEGylated drug delivery platforms are cutting-edge applications of PEG in the pharmaceutical field, especially in
siRNA drug delivery. In 2018, the first PEGylated siRNA therapeutic, Onpattro, was approved by FDA.
siRNA drugs have relatively large molecular weights and are negatively charged, making them less likely to cross
cell membranes to exert their effects. Moreover, they are easily degraded by enzymes and acids, resulting in poor
stability. PEGylated polymeric nanoparticles can improve the membrane penetration efficiency of siRNA drugs,
thus increasing the concentration of drugs in the cell and efficiently treating diseases.
▶ Passive targeting: PEGylation alters the adsorption of protein crowns on the surface of liposomes, significantly
prolongs the blood circulation time of liposomes, improves the biodistribution of drugs, and achieves passive
targeting of tumors by exploiting the enhanced permeability and retention (EPR) effect at tumor sites;
▶ Active targeting: PEG can be linked to specific targets to improve drug targeting and realize active targeting.

7. Huateng Pharma https://us.huatengsci.com/
7
Figure 3. Passive and active targeting [2]
Challenges
1. Anti-PEG antibodies
Recent studies challenge the historical perception of PEG as biologically inert, revealing 20%–70% of individuals
without known PEG exposure possess anti-PEG antibodies. Daily exposure to PEG in products like cosmetics
leads to pre-existing anti-PEG antibodies in many. This phenomenon contributes to reported loss of therapeutic
efficacy in PEGylated treatments, inducing immune responses that accelerate blood clearance and reduce half-life.
Hypersensitivity reactions, observed in PEGylated drugs like Jivi™ and Doxil®, underscore risks associated with
PEG components. PEG-related allergic reactions, noted in Pfizer/BioNTech BNT162b2 and Moderna mRNA-1273
vaccines, involve symptoms such as hives and anaphylaxis.
2. Heterogeneity of PEGylated drugs
PEGylation has advanced considerably in three decades, progressing from random multi-PEGylation to precise
site-specific applications with varied PEG types. Yet, persistent challenges remain. The polydisperse nature of
commercial PEGs, spanning broad molecular weights, impacts PEGylated therapies, amplifying heterogeneity if
multiple PEGs randomly attach. This diversity leads to batch variability, affecting crucial properties like solubility,
clearance rates, posing manufacturing and regulatory hurdles. The pursuit of high molecular
weight monodisperse PEGs, crucial for homogenous PEGylated therapeutics, emerges as a pressing goal, albeit
limited availability in commercial low-weight variants, marking a pivotal focus in recent PEGylation research.
Conclusion
In the future, PEGylation will remain pivotal for new therapeutic agents, not just extending half-lives but offering
broader benefits. Macromolecular drug expansion—proteins, peptides—and emerging LNP encapsulated mRNA
therapies will propel the field. PEGylation's role in novel therapies like immunotherapies, combinational
therapeutic agents on a single PEG molecule, is crucial. Progress hinges on synthesizing varied monodispersed
PEGs and existing clinical-grade PEG products and chemistries. Ultimately, PEGylation promises immense

8. Huateng Pharma https://us.huatengsci.com/
8
innovation in therapeutic development, backed by advancements in diverse PEG architectures and established
clinical practices.
Huateng Pharma, as a leading PEG linker supplier, can provide you with both polydispersed PEGs, monodispersed
PEGs and multi-arm PEGs for your drug PEGylation need. We are ISO 9001 and EXCiPACT GMP certified, contact
us at sales@huatengusa.com for your PEG inquiries.
References:
[1] Gao, Y, Joshi, M, Zhao, Z, Mitragotri, S. PEGylated therapeutics in the clinic. Bioeng Transl Med. 2023; 1-28.
doi:10.1002/btm2.10600
[2] Prajna Mishra, Bismita Nayak, R.K. Dey, PEGylation in anti-cancer therapy: An overview, Asian Journal of
Pharmaceutical Sciences, Volume 11, Issue 3, 2016, Pages 337-348, ISSN
1818-0876, https://doi.org/10.1016/j.ajps.2015.08.011.