Polyethylene Glycol (PEG) is a general term for ethylene glycol polymers with relative molecular weights of 200-8000 and above, which have different physicochemical properties depending on their molecular weights and structures. It has excellent lubricant, moisturizing, dispersing and adhesive properties, and can be used as antistatic agent and softener, etc. It is widely used in cosmetics, pharmaceutical, chemical fiber, rubber, plastic, paper, paint, electroplating, pesticide, metal processing and food processing industries.
What Are PEG Linkers?
Through chemical synthesis, PEG linkers can be made by precisely introducing functionalized groups with high reactivity at specific molecular ends of PEG. Since a variety of groups can be introduced, PEG linkers are widely used in biological and medical research due to their water solubility, excellent biocompatibility, and non-immunogenicity.
There are two classes of PEG linkers: monodispersed and polydispersed PEG linkers. The molecular weight of polydisperse PEG is uncertain and distributed in a certain range. Often polydispersity index (PDI) is used to determine how narrow the molecular weight distribution is. In the country, Monodisperse PEG refers to polyethylene glycol (PEG) with a precise, discrete molecular weight (ie, with a fixed molecular weight rather than a range).
Related Articles: Classification of Polyethylene Glycol (PEG) - By Synthesis Geometry, By Molecular Weight Distribution, By Functional End Groups
Application of PEG Linkers
A long-acting drug is a traditional application of PEGylation, which has been clinically applied for more than 30 years and has gradually become the mainstream solution for long-acting drugs. As the research of PEGylation progresses, its application fields are widening, beyond peptide and protein drugs; it is also applied to small molecule drugs, ADC drug linker, gene-drug (siRNA, mRNA) delivery, and hydrogel-based devices, etc.
1. PEG in Long-Acting Drugs (Mainly Protein & Peptide Drugs)
In the 1970s, Professor Frank Davis of Rutgers University modified bovine serum albumin with PEG in order to reduce the immunogenicity of recombinant proteins, prolong their metabolism in vivo, and enhance protein activity. Since then, this technology has been widely used in many fields of biomedicine. In 1981, Professor Davis founded Enzon Pharmaceuticals, and in 1990, the FDA approved Adagen® (pegademase bovine), the world's first PEGylated drug for severe combined immunodeficiency disease. Since then, PEGylated ADA, IFN, CPT, rhG-CSF, L-asparaginase, and many other products have been introduced. To date, there are more than 40 FDA- or EU-approved PEGylated drugs on the market worldwide. Below, the table shows the FDA-approved PEGylated drugs up to 2026.
| List of PEGylated drugs approved by the FDA | ||||||
|---|---|---|---|---|---|---|
| Entry | Trade Name | Company | PEGylated entity | Indications | Average MW of PEGs | Approved Year |
| Proteins and Peptides | ||||||
| 1 | Yuviwel (navepegritide) | Ascendis Pharma | CNP prodrug | Achondroplasia | 40 kDa | 2026 |
| 2 | Loargys (pegzilarginase-nbln) | Immedica Pharma | human ARG1 enzyme | Arginase 1 Deficiency | 5 kDa | 2026 |
| 3 | YORVIPATH (Palopegteriparatide) |
Ascendis Pharma | parathyroid hormone | hypoparathyroidism | 2 x 20 kDa | 2024 |
| 4 | Izervay (avacincaptad pegol) |
Iveric Bio | ribonucleic acid aptamer | geographic atrophy (GA) | ~43 kDa | 2023 |
| 5 | Elfabrio (pegunigalsidase alfa-iwxj) |
Chiesi Global Rare Diseases/Protalix | recombinant human GLA enzyme | Fabry disease | ~2 kDa | 2023 |
| 6 | SYFOVRE (pegcetacoplan injection) | Apellis | Pentadecapeptide | geographic atrophy (GA) | 40 kDa | 2023 |
| 7 | Rolvedon (eflapegrastim-xnst) | Spectrum Pharmaceuticals | G-CSF | febrile neutropenia | 3.4 kDa | 2022 |
| 8 | Stimufend (pegfilgrastim-fpgk) | Fresenius Kabi | G-CSF | neutropenia | 20 kDa | 2022 |
| 9 | Fylnetra (pegfilgrastim-pbbk) | Amneal Pharmaceuticals LLC | G-CSF | neutropenia | 20 kDa | 2022 |
| 10 | BESREMi (ropeginterferon alfa-2b) | PharmaEssentia Corp | Interferon | polycythemia vera | 40 kDa | 2021 |
| 11 | Skytrofa (Lonapegsomatropin) | Ascendis | human growth hormone | Growth hormone deficiency | 4 x 10 kDa | 2021 |
| 12 | Empaveli (Pegcetacoplan) | Apellis | Pentadecapeptide | Paroxysmal nocturnal hemoglobinuria (PNH) | 40 kDa | 2021 |
| 13 | Nyvepria (pegfilgrastim-apgf) | Pfizer Inc. | G-CSF | Neutropenia Associated with Chemotherapy | 20 kDa | 2020 |
| 14 | Esperoct (turoctocog alfa pegol) | Novo Nordisk | recombinant antihemophilic factor | hemophilia A | 40 kDa | 2019 |
| 15 | Ziextenzo (pegfilgrastim-bmez) | Sandoz | G-CSF | infection during chemotherapy | 20 kDa | 2019 |
| 16 | Udenyca (Pegfilgrastim-cbqv Injection) | Coherus Biosciences | G-CSF | infection during chemotherapy | 20 kDa | 2018 |
| 17 | Palynziq (Pegvaliase) | BioMarin Pharmaceutical | recombinant phenylalanine ammonia lyase | phenylketonuria | ~ 9 X 20 kDa | 2018 |
| 18 | Revcovi (Elapegademase-lvlr) | Leadiant Bioscience | recombinant adenosine deaminase | ADA-SCID | 80 kDa | 2018 |
| 19 | Fulphila (pegfilgrastim-jmdb) | Mylan GmbH | G-CSF | infection during chemotherapy | 20 kDa | 2018 |
| 20 | Asparlas (Calaspargase pegol) | Servier Pharma | L-asparaginase | leukemia | 31-39 x 5 kDa | 2018 |
| 21 | Jivi (Damoctocog alfa pegol) | Bayer Healthcare | recombinant antihemophilic factor | hemophilia A | 2 X 30 kDa | 2017 |
| 22 | Rebinyn | Novo Nordisk | recombinant coagulation factor lX | hemophilia B | 40 kDa | 2017 |
| 23 | Adynovate | Baxalta | recombinant antihemophilic factor | hemophilia A | ≥1 X 20 kDa | 2015 |
| 24 | Plegridy (peginterferon beta-1a) | Biogen | peginterferon beta-1a | multiple sclerosis | 20 kDa | 2014 |
| 25 | Omontys (Peginesatide ) | Takeda | erythropoietin | anemia | 2 X 20 kDa | 2012 |
| 26 | Sylatron (Peginterferon alfa-2b) | Merck | peginterferon-alfa-2b | melanoma | 12 kDa | 2011 |
| 27 | Krystexxa (Pegloticase) | Horizon Pharma | recombinant uricase protein | gout | 40 X 10 kDa | 2010 |
| 28 | Cimzia (Certolizumab pegol) | UCB | antitumor necrosis factor | rheumatoid arthritis | 40 kDa | 2008 |
| 29 | Mircera | Roche | erythropoietin | anemia | 30 kDa | 2007 |
| 30 | Macugen (Pegaptanib) | Pfizer | aptamer | macular degeneration | 2 X 20 kDa | 2004 |
| 31 | Somavert (Pegvisomant) | Pfizer | human growth hormone | acromegaly | 4-6 X 5 kDa | 2003 |
| 32 | Neulasta (Pegfilgrastim) | Amgen | G-CSF | infection during chemotherapy | 20 kDa | 2002 |
| 33 | Pegasys (Peginterferon alfa-2a) | Roche | peginterferon-alfa-2a | hepatitis B and C | 40 kDa | 2002 |
| 34 | Pegintron (Peginterferon alfa-2b) | Schering | peginterferon-alfa-2b | hepatitis C, melanoma | 12 kDa | 2001 |
| 35 | Oncaspar (Pegaspargase) | Enzon | asparaginase | leukemia | 69-82 X 5 kDa | 1994 |
| 36 | Adagen (pegademase bovine) | Enzon | adenosine deaminase | ADA-SCIO | 11-17 X 5 kDa | 1990 |
| Small Molecular Drugs | ||||||
| 37 | Movantik (Naloxegol) | AstraZeneca | naloxone | constipation | 339 Da | 2014 |
| 38 | Asclera (polidocanol) | Chemische Fabrik Kreussler & Co. | dodecanol | varicose veins | 400Da | 2010 |
| Nanoparticles | ||||||
| 39 | Doxil (Doxorubicin) | Schering | liposomal | ovarian cancer, multiple myeloma | 2 kDa | 1995 |
| 40 | Onivyde (irinotecan liposomal) | Merrimack Pharmaceuticals, Inc. | liposomal | Pancreatic Cancer | 2 kDa | 2015 |
| 41 | Onpattro® (Patisiran) | Alnylam Pharmaceuticals | LNPs | Polyneuropathy of hereditary transthyretin-mediated amyloidosis | 2 kDa | 2018 |
| 42 | Comirnaty™ | BioNTech/Pfizer | lipid nanoparticles | Prevention of COVID-19 | 2 kDa | 2020 |
| 43 | Spikevax® | Moderna | lipid nanoparticles | Prevention of COVID-19 | 2 kDa | 2020 |
| The list of drugs containing peg is indicated (number of units) x (MW of each PEG unit). G-CSF: growth colony-stimulating factor. | ||||||
| ADA-SCIO: adenosine deaminase severe combined immune deficiency. | ||||||
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References:
[1] Lawrence, Billings, et al., "Conjugation Strategy Strongly Impacts the Conformational Stability of a PEG-Protein Conjugate", ACS chemical biology, 11, 17, (2016): 1805-1809, https://pubs.acs.org/doi/abs/10.1021/acschembio.6b00349
[2] Kalyanram, Puri, et al., "Understanding the Stealth Properties of PEGylated lipids: A Mini-Review", International Journal of Lipids, 1, 2, (2020): xxx-xxx,https://openaccesspub.org/article/1432/ijl-20-3457.pdf
[3] Tolcher, "Antibody drug conjugates: lessons from 20 years of clinical experience", Annals of Oncology, 27, 12, (2016): 2168-2172,https://pubmed.ncbi.nlm.nih.gov/27733376/
[4] Buschmann, et. al., "Nanomaterial Delivery Systems for mRNA Vaccines", Vaccines, 9, 1, (2021): 65, https://doi.org/10.3390/vaccines9010065
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