Wikipedia

PEGylation

(Redirected from Pegylated)
This article is about PEGylation in a pharmaceutical context. For the bulk industrial process, see Ethoxylation.

PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein or vesicle, which is then described as PEGylated.[1][2][3][4] PEGylation affects the resulting derivatives or aggregates interactions, which typically slows down their coalescence and degradation as well as elimination in vivo.[5][6]

Polyethylene glycol

PEGylation is routinely achieved by the incubation of a reactive derivative of PEG with the target molecule. The covalent attachment of PEG to a drug or therapeutic protein can "mask" the agent from the host's immune system (reducing immunogenicity and antigenicity), and increase its hydrodynamic size (size in solution), which prolongs its circulatory time by reducing renal clearance. PEGylation can also provide water solubility to hydrophobic drugs and proteins. Having proven its pharmacological advantages and acceptability, PEGylation technology is the foundation of a growing multibillion-dollar industry.[7]

Methodology

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A comparison of uricase and PEG-uricase; PEG-uricase includes 40 polymers of 10kDa PEG. PEGylation improves its solubility at physiological pH, increases serum half-life and reduces immunogenicity without compromising activity. Upper images show the whole tetramer, lower images show one of the lysines that is PEGylated. (uricase from PDB: 1uox​ and PEG-uricase model from reference;[8] only 36 PEG polymers included)

PEGylation is the process of attaching the strands of the polymer PEG to molecules, most typically peptides, proteins, and antibody fragments, that can improve the safety and efficiency of many therapeutics.[9][10] It produces alterations in the physiochemical properties including changes in conformation, electrostatic binding, hydrophobicity etc. These physical and chemical changes increase systemic retention of the therapeutic agent. Also, it can influence the binding affinity of the therapeutic moiety to the cell receptors and can alter the absorption and distribution patterns.

PEGylation, by increasing the molecular weight of a molecule, can impart several significant pharmacological advantages over the unmodified form, such as improved drug solubility, reduced dosage frequency with potentially reduced toxicity and without diminished efficacy, extended circulating life, increased drug stability, and enhanced protection from proteolytic degradation; PEGylated forms may also be eligible for patent protection.[11]

PEGylated drugs

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The attachment of an inert and hydrophilic polymer was first reported around 1970 to extend blood life and control immunogenicity of proteins.[12] Polyethylene glycol was chosen as the polymer.[13][14] In 1981 Davis and Abuchowski founded Enzon, Inc., which brought three PEGylated drugs to market. Abuchowski later founded and is CEO of Prolong Pharmaceuticals.[15]

The clinical value of PEGylation is now well established. ADAGEN (pegademase bovine) 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. It is used to treat a form of severe combined immunodeficiency syndrome (ADA-SCID), as an alternative to bone marrow transplantation and enzyme replacement by gene therapy. Since the introduction of ADAGEN, a large number of PEGylated protein and peptide pharmaceuticals have followed and many others are under clinical trial or under development stages. Sales of the two most successful products, Pegasys and Neulasta, exceeded $5 billion in 2011.[16][17] All commercially available PEGylated pharmaceuticals contain methoxypoly(ethylene glycol) or mPEG. PEGylated pharmaceuticals on the market (in reverse chronology by FDA approval year) have included:[18]

Patent litigation

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The PEGylated lipid nanoparticle drug delivery (LNP) system of the mRNA vaccine known as mRNA-1273 has been the subject of ongoing patent litigation with Arbutus Biopharma, from whom Moderna had previously licensed LNP technology.[25][26] On 4 September 2020, Nature Biotechnology reported that Moderna had lost a key challenge in the ongoing case.[27]

Use in research

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PEGylation has practical uses in biotechnology for protein delivery,[28] cell transfection, and gene editing in non-human cells.[29]

Process

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The first step of the PEGylation is the suitable functionalization of the PEG polymer at one or both ends. PEGs that are activated at each end with the same reactive moiety are known as "homobifunctional", whereas if the functional groups present are different, then the PEG derivative is referred as "heterobifunctional" or "heterofunctional". The chemically active or activated derivatives of the PEG polymer are prepared to attach the PEG to the desired molecule.[30]

The overall PEGylation processes used to date for protein conjugation can be broadly classified into two types, namely a solution phase batch process and an on-column fed-batch process.[31] The simple and commonly adopted batch process involves the mixing of reagents together in a suitable buffer solution, preferably at a temperature between 4 and 6 °C, followed by the separation and purification of the desired product using a suitable technique based on its physicochemical properties, including size exclusion chromatography (SEC), ion exchange chromatography (IEX), hydrophobic interaction chromatography (HIC) and membranes or aqueous two-phase systems (ATPS).[32][33]

The choice of the suitable functional group for the PEG derivative is based on the type of available reactive group on the molecule that will be coupled to the PEG. For proteins, typical reactive amino acids include lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine and tyrosine. The N-terminal amino group and the C-terminal carboxylic acid can also be used as a site specific site by conjugation with aldehyde functional polymers.[34]

The techniques used to form first generation PEG derivatives are generally reacting the PEG polymer with a group that is reactive with hydroxyl groups, typically anhydrides, acid chlorides, chloroformates and carbonates. In the second generation PEGylation chemistry more efficient functional groups such as aldehyde, esters, amides etc. are made available for conjugation.

As applications of PEGylation have become more and more advanced and sophisticated, there has been an increase in need for heterobifunctional PEGs for conjugation. These heterobifunctional PEGs are very useful in linking two entities, where a hydrophilic, flexible and biocompatible spacer is needed. Preferred end groups for heterobifunctional PEGs are maleimide, vinyl sulfones, pyridyl disulfide, amine, carboxylic acids and NHS esters.[35][36][37]

Third-generation pegylation agents, where the polymer has been branched, Y-shaped or comb-shaped are available and show reduced viscosity and lack of organ accumulation.[38] Recently also enzymatic approaches of PEGylation have been developed, thus further expanding the conjugation tools.[39][40] PEG-protein conjugates obtained by enzymatic methods are already in clinical use, for example: Lipegfilgrastim, Rebinyn, Esperoct.

Limitations

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Unpredictability in clearance times for PEGylated compounds may lead to the accumulation of large-molecular-weight compounds in the liver leading to inclusion bodies with no known toxicologic consequences.[41] Furthermore, alteration in the chain length may lead to unexpected clearance times in vivo.[42] Moreover, the experimental conditions of PEGylation reaction (i.e. pH, temperature, reaction time, overall cost of the process and molar ratio between PEG derivative and peptide) also have an impact on the stability of the final PEGylated products.[43] To overcome the above-mentioned limitations different strategies such as changing the size (Mw), the number, the location and the type of linkage of PEG molecule were offered by several researchers.[44][45] Conjugation to biodegradable polysaccharides, which is a promising alternative to PEGylation, is another way to solve the biodegradability issue of PEG.[46]

See also

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References

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  1. ^ Jokerst, Jesse V; Lobovkina, Tatsiana; Zare, Richard N; Gambhir, Sanjiv S (June 2011). "Nanoparticle PEGylation for imaging and therapy". Nanomedicine. 6 (4): 715–728. doi:10.2217/nnm.11.19. PMC 3217316. PMID 21718180.
  2. ^ Knop, Katrin; Hoogenboom, Richard; Fischer, Dagmar; Schubert, Ulrich S. (23 August 2010). "Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives". Angewandte Chemie International Edition. 49 (36): 6288–6308. doi:10.1002/anie.200902672. PMID 20648499.
  3. ^ Veronese, Francesco M; Mero, Anna (2008). "The Impact of PEGylation on Biological Therapies". BioDrugs. 22 (5): 315–329. doi:10.2165/00063030-200822050-00004. PMID 18778113. S2CID 23901382.
  4. ^ Veronese, Francesco M.; Pasut, Gianfranco (November 2005). "PEGylation, successful approach to drug delivery". Drug Discovery Today. 10 (21): 1451–1458. doi:10.1016/S1359-6446(05)03575-0. PMID 16243265.
  5. ^ Blume G, Cevc, G (13 April 1990). "Liposomes for the sustained drug release in vivo". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1029 (1): 91–97. doi:10.1016/0005-2736(90)90440-y. PMID 2223816.
  6. ^ Klibanov AL, Maruyama K, Torchilin VP, Huang L (30 July 1990). "Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes". FEBS Lett. 268 (1): 235–237. doi:10.1016/0014-5793(90)81016-h. PMID 2384160. S2CID 11437990.
  7. ^ Damodaran V. B.; Fee C. J. (2010). "Protein PEGylation: An overview of chemistry and process considerations". European Pharmaceutical Review. 15 (1): 18–26.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Sherman, MR; Saifer, MG; Perez-Ruiz, F (3 January 2008). "PEG-uricase in the management of treatment-resistant gout and hyperuricemia". Advanced Drug Delivery Reviews. 60 (1): 59–68. doi:10.1016/j.addr.2007.06.011. PMID 17826865.
  9. ^ Veronese, FM; Harris, JM (June 2002). "Introduction and overview of peptide and protein pegylation". Advanced Drug Delivery Reviews. 54 (4): 453–456. doi:10.1016/s0169-409x(02)00020-0. PMID 12052707.
  10. ^ Porfiryeva, N. N.; Moustafine, R. I.; Khutoryanskiy, V. V. (January 2020). "PEGylated Systems in Pharmaceutics" (PDF). Polymer Science, Series C. 62 (1): 62–74. doi:10.1134/S181123822001004X. S2CID 226664780.
  11. ^ Milla, P; Dosio, F (13 January 2012). "PEGylation of proteins and liposomes: a powerful and flexible strategy to improve the drug delivery". Current Drug Metabolism. 13 (1): 105–119. doi:10.2174/138920012798356934. hdl:2318/86788. PMID 21892917.
  12. ^ Davis, Frank F. (June 2002). "The origin of pegnology". Advanced Drug Delivery Reviews. 54 (4): 457–458. doi:10.1016/s0169-409x(02)00021-2. PMID 12052708.
  13. ^ Abuchowski, A; Van Es, T; Palczuk, N. C.; Davis, F. F. (1977). "Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol". The Journal of Biological Chemistry. 252 (11): 3578–81. doi:10.1016/S0021-9258(17)40291-2. PMID 405385.
  14. ^ Abuchowski, A; McCoy, J. R.; Palczuk, N. C.; Van Es, T; Davis, F. F. (1977). "Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase". The Journal of Biological Chemistry. 252 (11): 3582–6. doi:10.1016/S0021-9258(17)40292-4. PMID 16907.
  15. ^ "Dr. Abraham Abuchowski, Ph.D. – Home". prolongpharma.com. Retrieved 2020-01-15.
  16. ^ Klauser, Alexander (Head), Roche Group Media Relations, "Roche in 2011: Strong results and positive outlook," www.roche.com/med-cor-2012-02-01-e.pdf, Feb 1, 2012, p.7
  17. ^ "Amgen 2011 Annual Report and Financial Summary," [1] 2011 AnnualReport.pdf, Feb 23 2012, p. 71
  18. ^ Zalipsky, Samuel; Pasut, Gianfranco (2020). "Evolution of polymer conjugation to proteins". Polymer-Protein Conjugates. pp. 3–22. doi:10.1016/b978-0-444-64081-9.00001-2. ISBN 9780444640819. S2CID 209731201.
  19. ^ Cabanillas, Beatriz; Akdis, Cezmi; Novak, Natalija (2020). "Allergic reactions to the first COVID-19 vaccine: A potential role of Polyethylene glycol?". Allergy. 76 (6): 1617–1618. doi:10.1111/all.14711. PMID 33320974. S2CID 229284320.
  20. ^ Weiland, Noah; LaFraniere, Sharon; Baker, Mike; Thomas, Katie (17 December 2020). "2 Alaska Health Workers Got Emergency Treatment After Receiving Pfizer's Vaccine". New York Times.
  21. ^ Firger, Jessica; Caldwell, Travis (19 December 2020). "Third Alaskan health care worker has allergic reaction to Covid-19 vaccine". Cable News Network.
  22. ^ Powers, Marie (May 29, 2018). "Biomarin aces final exam: Palynziq gains FDA approval to treat PKU in adults". BioWorld.
  23. ^ Levy, Harvey L.; Sarkissian, Christineh N.; Stevens, Raymond C.; Scriver, Charles R. (June 2018). "Phenylalanine ammonia lyase (PAL): From discovery to enzyme substitution therapy for phenylketonuria". Molecular Genetics and Metabolism. 124 (4): 223–229. doi:10.1016/j.ymgme.2018.06.002. PMID 29941359. S2CID 49411168.
  24. ^ "FDA approves modified antihemophilic factor for hemophilia A". www.fda.gov. Archived from the original on 2015-11-16.
  25. ^ Auth DR, Powell MB (14 September 2020). "Patent Issues Highlight Risks of Moderna's COVID-19 Vaccine". New York Law Journal. Retrieved 1 December 2020.
  26. ^ Vardi N (29 June 2020). "Moderna's Mysterious Coronavirus Vaccine Delivery System". Forbes. Retrieved 1 December 2020.
  27. ^ "Moderna loses key patent challenge". Nature Biotechnology. 38 (9): 1009. September 2020. doi:10.1038/s41587-020-0674-1. PMID 32887970. S2CID 221504018.
  28. ^ Pasut, Gianfranco; Zalipsky, Samuel (2020). Polymer-Protein Conjugates: From Pegylation and Beyond. Elsevier. ISBN 978-0-444-64082-6. OCLC 1127111107.[page needed]
  29. ^ Balazs, Daniel A.; Godbey, WT (15 December 2011). "Liposomes for Use in Gene Delivery". Journal of Drug Delivery. 2011: 326497. doi:10.1155/2011/326497. PMC 3066571. PMID 21490748.
  30. ^ Pasut, Gianfranco; Veronese, Francesco M. (July 2012). "State of the art in PEGylation: The great versatility achieved after forty years of research". Journal of Controlled Release. 161 (2): 461–472. doi:10.1016/j.jconrel.2011.10.037. PMID 22094104.
  31. ^ Fee, Conan J.; Van Alstine, James M. (2006). "PEG-proteins: Reaction engineering and separation issues". Chemical Engineering Science. 61 (3): 924. CiteSeerX 10.1.1.509.2865. doi:10.1016/j.ces.2005.04.040.
  32. ^ Veronese, Francesco M., ed. (2009). "Protein conjugates purification and characterization". PEGylated protein drugs basic science and clinical applications (Online-Ausg. ed.). Basel: Birkhäuser. pp. 113–125. ISBN 978-3-7643-8679-5.
  33. ^ Fee, Conan J. (2003). "Size-exclusion reaction chromatography (SERC): A new technique for protein PEGylation". Biotechnology and Bioengineering. 82 (2): 200–6. doi:10.1002/bit.10561. hdl:10092/351. PMID 12584761.
  34. ^ Fee, Conan J.; Damodaran, Vinod B. (2012). "Production of PEGylated Proteins". Biopharmaceutical Production Technology. p. 199. doi:10.1002/9783527653096.ch7. ISBN 9783527653096.
  35. ^ "Polypeptide therapeutics and uses thereof". Wipo (PCT). WO (138413A1). 2016.
  36. ^ "Methods and pharmaceutical compositions for treating candida auris in blood". Wipo (PCT). WO (126695A2). 2019.
  37. ^ "Arginase formulations and methods". Wipo (PCT). WO (8495A2). 2011.
  38. ^ Ryan, Sinéad M; Mantovani, Giuseppe; Wang, Xuexuan; Haddleton, David M; Brayden, David J (2008). "Advances in PEGylation of important biotech molecules: Delivery aspects". Expert Opinion on Drug Delivery. 5 (4): 371–83. doi:10.1517/17425247.5.4.371. PMID 18426380. S2CID 97373496.
  39. ^ Maso, Katia; Grigoletto, Antonella; Pasut, Gianfranco (2018). "Transglutaminase and Sialyltransferase Enzymatic Approaches for Polymer Conjugation to Proteins". Therapeutic Proteins and Peptides. Advances in Protein Chemistry and Structural Biology. Vol. 112. pp. 123–142. doi:10.1016/bs.apcsb.2018.01.003. ISBN 9780128143407. PMID 29680235.
  40. ^ da Silva Freitas, Débora; Mero, Anna; Pasut, Gianfranco (20 March 2013). "Chemical and Enzymatic Site Specific PEGylation of hGH". Bioconjugate Chemistry. 24 (3): 456–463. doi:10.1021/bc300863y. hdl:11577/2574695. PMID 23432141.
  41. ^ Kawai, F. (1 January 2002). "Microbial degradation of polyethers". Applied Microbiology and Biotechnology. 58 (1): 30–38. doi:10.1007/s00253-001-0850-2. PMID 11831473. S2CID 7600787.
  42. ^ Veronese, Francesco M (March 2001). "Peptide and protein PEGylation". Biomaterials. 22 (5): 405–417. doi:10.1016/s0142-9612(00)00193-9. PMID 11214751.
  43. ^ González-Valdez, José; Rito-Palomares, Marco; Benavides, Jorge (June 2012). "Advances and trends in the design, analysis, and characterization of polymer–protein conjugates for 'PEGylaided' bioprocesses". Analytical and Bioanalytical Chemistry. 403 (8): 2225–2235. doi:10.1007/s00216-012-5845-6. PMID 22367287. S2CID 22642574.
  44. ^ Zhang, Genghui; Han, Baozhong; Lin, Xiaoyan; Wu, Xin; Yan, Husheng (December 2008). "Modification of Antimicrobial Peptide with Low Molar Mass Poly(ethylene glycol)". The Journal of Biochemistry. 144 (6): 781–788. doi:10.1093/jb/mvn134. PMID 18845567.
  45. ^ Obuobi, Sybil; Wang, Ying; Khara, Jasmeet Singh; Riegger, Andreas; Kuan, Seah Ling; Ee, Pui Lai Rachel (October 2018). "Antimicrobial and Anti-Biofilm Activities of Surface Engineered Polycationic Albumin Nanoparticles with Reduced Hemolytic Activity". Macromolecular Bioscience. 18 (10): 1800196. doi:10.1002/mabi.201800196. PMID 30066983. S2CID 51888683.
  46. ^ Zhou, Yang; Petrova, Stella P.; Edgar, Kevin J. (2021-11-15). "Chemical synthesis of polysaccharide–protein and polysaccharide–peptide conjugates: A review". Carbohydrate Polymers. 274: 118662. doi:10.1016/j.carbpol.2021.118662. ISSN 0144-8617. PMID 34702481. S2CID 239999294.
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Scholia has a profile for PEGylation (Q682252).
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