PEG for drug development

February 17, 2025

Wide applications of polyethylene glycol (PEG)

Polyethylene glycol (PEG) is a polymer material that is usually soluble in water and many organic solvents, but insoluble in fatty hydrocarbons, benzene, ethylene glycol, etc. It does not hydrolyze or deteriorate and has a wide range of solubility, excellent compatibility, stability, lubricity, film-forming ability, plasticity, and dispersibility. It is a low-toxicity substance with no irritant properties, and it is a non-ionic polymer. PEG has extensive applications across various industries, including cosmetics, synthetic fibers, rubber, plastics, papermaking, paint, electroplating, pesticides, metal processing, and food processing. In addition, it is used in the pharmaceutical industry for covalent modification of proteins and peptides.

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Effective approaches to improve the physicochemical properties of drugs

PEGylation is the process of covalently attaching activated polyethylene glycol (PEG) to proteins or peptide molecules through chemical methods. Since Davis first used PEG to modify bovine serum albumin in 1977, PEGylation technology has been widely applied in research and applications to improve the physicochemical properties and biological activity of proteins (peptides), enzymes, antibodies, and small-molecule drugs.

PEG itself has advantages such as non-toxicity, non-immunogenicity, non-antigenicity, and good water solubility. PEGylation can alter the drug’s conformation, electrostatic binding ability, hydrophilicity/hydrophobicity, and other physicochemical properties, thereby increasing the drug’s in vivo retention time, enhancing the plasma half-life, prolonging absorption time, improving the drug’s affinity with cell receptors, and studies show that PEGylation can also enhance the drug’s tumor targeting. Based on these characteristics, PEG is often used in drug delivery and modification technologies, either by directly conjugating with the drug or by being attached to the drug surface and encapsulated in nanomaterials.

In practice, PEGylated drugs can reduce dosing frequency, improve efficacy, enhance tolerance, reduce immunogenicity/antigenicity, improve pharmacokinetics and toxicity, and reduce the incidence of adverse events. Additionally, PEG can increase protein solubility and stability, which is beneficial for drug production and storage.

The Advantages of PEGylation — Advantages of PEGylation

Currently, PEGylation has become a well-established technology for extending the half-life of drugs in clinical practice. Its safety has been fully validated through years of clinical use and has been approved by the regulatory authorities in most countries/regions for intravenous, oral, and topical use.

Pharmacodynamics and pharmacokinetics of PEGylated molecules

The absorption of PEG molecules depends on the administration route. Due to the relatively large size of PEG molecules, they are not easily absorbed through the gastrointestinal tract into the bloodstream. The absorption rate for transdermal administration is related to the molecular weight of PEG; if the molecular weight is too large, it is difficult for the molecule to be absorbed by epithelial cells through paracellular transport or endocytosis. Similarly, subcutaneous and intramuscular injections also exhibit molecular weight-dependent properties.

PEGylation can significantly improve the circulation time of drug molecules. PEG molecules can adsorb water molecules, expanding the volume of PEGylated large molecules by 5-10 times. This can effectively reduce the degradation rate of the corresponding protein or peptide by hydrolytic enzymes, thereby extending its half-life in the body and further improving the distribution of protein and peptide molecules in vivo. For example, PEGylation of GLP-1 significantly improved the rate of insulin release in the body, with Lys-PEGylation-GLP-1 having a 40-fold, 10-fold, and 28-fold extended half-life in plasma, liver, and kidneys, respectively, overall improving the molecular bioavailability.

The steric hindrance of PEGylated molecules can effectively shield plasma enzymes and reduce phagocytosis by the reticuloendothelial system (RES), thus regulating the pharmacokinetics. On the other hand, the steric hindrance may decrease the drug’s affinity for its target, resulting in a loss of some efficacy, but this is counterbalanced by the extended drug circulation half-life. Therefore, the effect of PEGylation is essentially to re-establish a balance between pharmacodynamics and pharmacokinetics.

Moreover, PEGylation can be used to modulate the immunogenicity of drugs. By binding to the non-active essential groups of the drug, PEG forms a shield on the surface, making its epitopes less recognizable and preventing the production of corresponding antibodies, thus inhibiting the immune response.

in vivo properties of PEG: absorption, metabolism, distribution and metabolism — PEG in vivo properties: absorption, metabolism, distribution and metabolism

Successful PEGylated Cases

Given that PEGylation can effectively improve the pharmacodynamics and pharmacokinetics of drugs, some drugs have used PEGylation in their design to overcome inherent shortcomings of natural molecules in clinical use, leading to significant commercial success.

Certolizumab Pegol

Certolizumab Pegol (brand name: Cimzia) is a tumor necrosis factor (TNF) blocker and a PEGylated humanized Fab fragment monoclonal antibody against INF-α. The attachment of 40kDa PEG prolongs the plasma elimination half-life of Certolizumab Pegol. Certolizumab Pegol lacks the Fc fragment, meaning it cannot anchor complement or induce antibody-dependent cell-mediated cytotoxicity. In vitro, it does not induce programmed cell death in human peripheral blood-derived monocytes or lymphocytes, nor does it induce neutrophil degranulation.

A randomized, double-blind, placebo-controlled trial with 662 patients showed that the clinical response rate and clinical symptom relief in patients using Certolizumab Pegol were significantly higher than those receiving placebo. The FDA approved Certolizumab Pegol for marketing in 2008, initially for Crohn’s disease, and later expanded to rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. After its market release, Certolizumab Pegol’s global sales rapidly climbed, reaching $1.92 billion in 2019.

Pegfilgrastim (PEGylated Filgrastim)

Filgrastim (brand name: Neupogen) was developed by Amgen and approved by the FDA in 1991, with its patent expiring in 2006. Filgrastim is a cell growth factor (rhG-CSF) produced by Escherichia coli that regulates neutrophils in the bone marrow, promoting the proliferation and differentiation of neutrophil precursors. It is used to treat congenital neutropenia, cyclical neutropenia, idiopathic neutropenia, and neutropenia associated with bone marrow transplantation or chemotherapy.

PEGylated filgrastim (Pegfilgrastim) is a long-acting form of filgrastim, created by covalently attaching PEG to the N-terminal methionine of rhG-CSF. PEGylation reduces the renal clearance of rhG-CSF, decreases cellular uptake of the drug molecule, and reduces protein hydrolysis, significantly extending the half-life of PEGylated filgrastim. The pharmacodynamics and adverse event profile of PEGylated filgrastim are comparable to or even better than those of filgrastim.

Based on this, the FDA approved PEGylated filgrastim (brand name: Neulasta) for marketing in 2002, and in 2011, the NMPA approved the PEGylated rhG-CSF developed by CSPC (brand name: Jinyouli) for marketing, aimed at reducing the incidence of infections caused by febrile neutropenia after chemotherapy. In 2014, Neulasta’s sales reached $4.686 billion, but by 2019, the sales dropped to $3.22 billion, primarily due to increased competition from biosimilars.

PEGylated drug development pipeline and market approval

Trade names	API	Indication	Producer	Approval
Jivi	60K-PEG recombinant Factor VIII antihemophilic factor	Hemophilia A	Bayer	2018
Palynziq	2K-PEG-rhu-Phenylalanine ammonia-lyase, Pegvaliase-pqpz	Phenyl-ketonuria	Biomarin	2018
Reviloxis kita	40K-PEG-RNA aptamer + reverse agent, a Factor-IXa blocker, Pegnivacogin /Anivamersen	Anti-coagulation	Regado/Tobira	2016
Adynovate	20K-PEG-Factor VIII Antihemophilic Factor VIII	Hemophilia A	Baxalta	2015
Onivyde	2K-PEG-Liposomal irinotecan hydrochloride trihydrate	Metastatic pancreatic cancer	Ipsen	2015
Plegridy	20K-PEG-Interferon beta-1a	Relapsing forms of multiple sclerosis	Biogen	2014
Movantic	<1K-PEG-Naloxegol	Opioid-induced constipation	AstraZeneca	2014
Omontysb	40K-PEG-Erythropoietin-mimetic peptide, Peginesatide	Anemia associated with chronic kidney disease	Affymax/Takeda	2012
Sylatron™	12K-PEG-Interferon alpha 2b	Melanoma	Merck	2011
Krystexxacc	40K-PEG-Uricase, Pegloticase	Gout	Savient	2010
Cimzia	40K-PEG-Certolizumab	Rheumatoid arthritis, Crohn’s disease, Axial spondyloarthritis	Nektar/UCB Pharma	2008
Mircera	30K-PEG-erythropoietin (epoetin) beta	Anemia associated with chronic kidney disease	Hoffman-La Roche	2007
Macugen	40K-PEG-anti-VEGF aptamer, Pegaptanib	Age-related macular degeneration	Pfizer	2004
Somavert	5K-PEG-rhuGH (human growth hormone), Pegvisomant	Acromegaly	Pfizer	2003
Neulasta	20K-PEG-Granulocyte colony stimulating factor, Pegfilgrastim	Neutropenia	Amgen	2002
Pegasys	40K-PEG-interferon alpha-2	Hepatitis C and B	Hoffmann-La Roche	2001
PegIntron	12K-PEG-interferon alfa-2b	Hepatitis C and B	Schering-Plough/Enzon	2000
Doxil/Caelyx	2K-PEG-Liposomal doxorubicin HCl	Cancer	Alza	1995
Oncaspar	5K-PEGylated L-asparaginase, Pegaspargase	Acute lymphoblastic leukemia	Enzon	1994
Adagen	5K-PEG-adenosine deaminase (bovine), Pegademase	Severe combined immunodeficiency disease (SCID)	Enzon	1990

Many PEGylated protein drugs are now in clinical use, and PEGylated drugs that have already been marketed primarily include interferons, interleukins, tumor necrosis factors, and L-asparaginase. PEGylation enhances the pharmacokinetic profile of these drugs, extending their half-life, decreasing clearance rates, and reducing volume of distribution. This allows for reduced dosing frequency and drug quantity. Additionally, PEGylation helps reduce the immunogenicity of protein drugs. For example, L-asparaginase, used for treating acute lymphoblastic leukemia (ALL), has known side effects such as liver damage, central nervous system damage, coagulation factor reduction, and severe allergic reactions in about 20% of patients.

PEG-L-asparaginase has been shown to significantly reduce these side effects. Research indicates that patients allergic to L-asparaginase do not experience allergic reactions when treated with PEG-L-asparaginase. Furthermore, PEGylation significantly increases the half-life of L-asparaginase, reducing the required clinical dosage. In a clinical trial for pediatric ALL, PEG-L-asparaginase was administered at 2500 IU·m² every two weeks for 15 doses, while L-asparaginase was given at 25,000 IU·m² every week for 30 doses. Both groups had similar event-free survival rates, but the incidence of toxicity was significantly lower in the PEG-L-asparaginase group.

Active Pipeline in PEGylation

As technology and techniques improve, the pharmaceutical industry is increasingly focusing on the role of PEGylation in modulating drug efficacy and pharmacokinetics. The research pipeline for PEGylated drugs has become more active, with ongoing developments in several categories:

Cytokines (mainly biosimilars)

These include PEGylated forms of cytokines, with several biosimilar formulations being explored in the market.

Small Molecules

This includes PEGylated versions of small molecules like:

PEGylated Irinotecan (used in cancer therapy)

PEGylated Naloxone (used in opioid overdose treatment)

PEGylated Camptothecin (an anti-cancer agent)

PEGylated Doxorubicin (a chemotherapeutic agent)

PEGylated Gemcitabine (used in the treatment of cancer)

Antibodies

The use of PEGylation for monoclonal antibodies, including PEGylated Trastuzumab (Herceptin), has also been explored, along with various antibody fragments that benefit from extended circulation times due to PEGylation.

Summary

PEGylation has become an increasingly important tool for regulating drug efficacy and pharmacokinetics in the pharmaceutical industry. PEGylated drugs exhibit enhanced hydrophilicity, prolonged in vivo retention, increased systemic exposure, and extended absorption times. The steric hindrance introduced by PEGylation effectively reduces enzymatic degradation, extending the drug’s half-life and improving distribution. While it may slightly reduce a drug’s targeting affinity, the extended half-life compensates for this effect, achieving a new balance between efficacy and pharmacokinetics. Furthermore, PEGylation’s ability to decrease the immunogenicity and antigenicity of large molecules makes it a powerful tool for improving the therapeutic potential of protein drugs.

PEGylation Services at BOC Sciences

FDA, Formulation