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 under 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||Drug||Company||PEGylated entity||Indications||Average MW of PEGs||Approved Year|
|1||Besremi||PharmaEssentia Corp||Interferon||polycythemia vera||40 kDa||2021|
|2||Skytrofa||Ascendis||human growth hormone||Growth hormone deficiency||4 x 10 kDa||2021|
|3||Empaveli||Apellis||Pentadecapeptide||Paroxysmal nocturnal hemoglobinuria (PNH)||40 kDa||2021|
|4||Nyvepria||Pfizer Inc.||G-CSF||Neutropenia Associated with Chemotherapy||20 kDa||2020|
|5||Esperoct||Novo Nordisk||recombinant antihemophilic factor||hemophilia A||40 kDa||2019|
|6||Ziextenzo||Sandoz||G-CSF||infection during chemotherapy||20 kDa||2019|
|7||Udenyca||Coherus Biosciences||G-CSF||infection during chemotherapy||20 kDa||2018|
|8||Palynziq||BioMarin Pharmaceutical||recombinant phenylalanine ammonia lyase||phenylketonuria||~ 9 X 20 kDa||2018|
|9||Revcovi||Leadiant Bioscience||recombinant adenosine deaminase||ADA-SCID||80 kDa||2018|
|10||Fulphila||Mylan GmbH||G-CSF||infection during chemotherapy||20 kDa||2018|
|11||Asparlas||Servier Pharma||L-asparaginase||leukemia||31-39 x 5 kDa||2018|
|12||Jivi||Bayer Healthcare||recombinant antihemophilic factor||hemophilia A||2 X 30 kDa||2017|
|13||Rebinyn||Novo Nordisk||recombinant coagulation factor lX||hemophilia B||40 kDa||2017|
|14||Adynovate||Baxalta||recombinant antihemophilic factor||hemophilia A||≥1 X 20 kDa||2015|
|15||Plegridy||Biogen||peginterferon beta-1a||multiple sclerosis||20 kDa||2014|
|16||Omontys||Takeda||erythropoietin||anemia||2 X 20 kDa||2012|
|18||Krystexxa||Horizon Pharma||recombinant uricase protein||gout||40 X 10 kDa||2010|
|19||Cimzia||UCB||antitumor necrosis factor||rheumatoid arthritis||40 kDa||2008|
|21||Macugen||Pfizer||aptamer||macular degeneration||2 X 20 kDa||2004|
|22||Somavert||Pfizer||human growth hormone||acromegaly||4-6 X 5 kDa||2003|
|23||Neulasta||Amgen||G-CSF||infection during chemotherapy||20 kDa||2002|
|24||Pegasys||Roche||peginterferon-alfa-2a||hepatitis B and C||40 kDa||2002|
|25||Pegintron||Schering||peginterferon-alfa-2b||hepatitis C, melanoma||12 kDa||2001|
|26||Oncaspar||Enzon||asparaginase||leukemia||69-82 X 5 kDa||1994|
|27||Adagen||Enzon||adenosine deaminase||ADA-SCIO||11-17 X 5 kDa||1990|
|Small Molecular Drugs|
|29||Asclera||Chemische Fabrik Kreussler||dodecyl alcohol||varicose veins||400 Da||2010|
|30||Doxil||Schering||liposomal||ovarian cancer, multiple myeloma||2 kDa||1995|
|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. Modification of 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 is beneficial to improve the distribution of drugs 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 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.
Benefits of Monodisperse PEG Linkers in Drug Development
What is PEGylation? Things About PEGylation Technology and Biopharmaceuticals You Should Know
The Applications of PEGylation Reagents