What is PEGylation? What are the PEGylated drugs used for? PEGylation is the process of the strands attachment of the polymer PEG to molecules and macrostructures, such as a drug, therapeutic protein or vesicle, that can improve the safety and efficiency of many therapeutics. The chain binds to the drugs covalently and builds it sterically stable. Thus, the PEGylated proteins or peptides are non-toxic, non-antigenic, non-immunogenic, and highly water-soluble. In addition, it further increases the half-life of the PEGylated drugs and reduces dose frequency by preventing renal excretion of drugs.
PEGylation products consist of various reagents including linkers, cross-linkers, and labels. Different reagents include AMINE, CARBOXYL, and CARBOXYL PEGylation. The PEGylated drugs currently are used in the treatment of cancer, chronic kidney diseases, hepatitis, multiple sclerosis, hemophilia, and gastrointestinal disorders. ADAGEN manufactured by Enzon Pharmaceuticals, Inc., US was the first PEGylated protein approved by the U.S. Food and Drug Administration (FDA) in March 1990, to enter the market. Since the introduction of ADAGEN, a mass of PEGylated protein and peptide drugs have kept up the footsteps and many others are under clinical trial or development stages. Among the FDA-approved drugs, Pegasys and Neulasta, exceeded $5 billion in 2011. It's worth mentioning that all of the FDA-approved drugs contain methoxypoly (ethylene glycol) or mPEG. The list of PEGylated drugs approved by the FDA is shown below.
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 ComirnatyTM 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.
In summary, PEGylation has three main advantages:
▶ Improve pharmacokinetics and pharmacodynamic properties: Studies have shown that after PEGylation, the pharmacokinetic properties in the body will change significantly, including prolonging the plasma half-life, increasing the release of drugs in the body, reducing the renal clearance rate, etc. ▶ Enhance drug stability: After the PEGylation of proteins and peptides, a thicker hydration film will be formed on the surface to prevent aggregation and precipitation. Modifying the linkage between PEG and lipid derivatives (acyl, ether, disulfide bond, etc.) can also increase the stability of liposomes. In addition, the flexible chain of PEG can produce a steric hindrance effect, protect the modification from protease attack, and increase the stability of the modification. ▶ Improve the distribution of the drug in the body: After being modified by PEG, the molecular weight of the drug is increased, which greatly reduces its glomerular filtration effect during systemic administration, thereby reducing its excretion in urine. In addition, PEGylated drugs have improved stability in the systemic circulation and prolonged retention time, which enhances drug distribution in the body. In particular, it is beneficial to the accumulation of macromolecular drugs in tumors and inflammatory sites with retention-enhancing effects, thereby prolonging the treatment time of the drugs in vivo.
In recent years, with the continuous deepening of research and development, new PEGylated drugs such as modified drugs that use heterobifunctional PEG (X-PEG-Y) as a linker have come out. In the future, with the continuous improvement of modification technology, it is believed that more and more excellent PEGylated drugs will appear to provide patients with more and better treatment options.
Biochempeg provides high-quality PEG raw materials and PEGylation reagents. These reagents are water soluble, monodisperse, biocompatible, and almost aggregation-free, making them ideal for bioconjugation or crosslinking of proteins, antibodies, peptides, oligonucleotides, or solid surfaces to other macromolecules, therapeutic compounds or other small molecules, and dyes. Featured PEG Derivatives are listed below (Offer from milligram to kilogram scale). MF001021 - mPEG-EPO >>> HE002121 - OH-PEG-AA >>> HE003005 - SH-PEG-NH2 >>> HE003041 - SH-PEG-Biotin >>> MD005002 - NH2-PEG3-OH >>> MD005002 - NH2-PEG4-OH >>> MD005016 - NH2-PEG24-COOH >>> MD001005 - mPEG36-NH2 >>> MD006002 - N3-PEG4-OH >>> MD006002 - N3-PEG6-OH >>> MD006005 - N3-PEG11-NH2 >>> MD006016 - N3-PEG2-COOH >>> MD006025 - N3-PEG2-SPA >>> MD022023 - Mal-NH-PEG4-NHS >>> MD022067 - Mal-NH-PEG4-OtBu >>> MD068016 - Boc-NH-PEG12-COOH >>> MD068006 - Boc-NH-PEG11-N3 >>>
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