PEGylation

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In the so-called PEGylation , biopharmaceutical active ingredients or diagnostics are chemically linked ( conjugated ) with polyethylene glycol (PEG ). Chain-like structures are attached to the active substance or the diagnostic agent, which almost completely envelop it and thus reliably protect it against premature degradation by antibodies or the body's own enzymes , for example proteases . This “masking” enables the active ingredient (or the diagnostic agent) to withstand attacks by the immune system and enzymatic degradation processes, to reach its destination unhindered and to develop its therapeutic effect efficiently. In the case of biopharmaceutical active ingredients in particular, PEGylation is a very efficient process for a significant reduction in immunogenicity , for significantly higher protease stability and significantly slower renal excretion (via the kidneys).

Mechanism of action

In the 1970s, Davis, Abuchowski, et al. a. the method for conjugating polyethylene glycol (PEG) with proteins. The process is state-of-the-art today and is used for a large number of biopharmaceutical active ingredients and diagnostics in production as well as in research and development. Essentially, peptides , proteins and antibodies and their fragments as well as aptamers are PEGylated . The PEGylation increases the safety and efficiency of these therapeutics. PEGylation changes the physicochemical properties, such as the conformation , the electrostatic binding forces and the hydrophilicity . These physical and chemical changes increase the systemic retention of the therapeutic. The binding affinity of the therapeutic agent to cell receptors and the uptake and distribution of active substances can also be significantly influenced.

Benefits of PEGylation

PEGylation increases the molecular weight of the active ingredient and can imply some significant pharmacological advantages over the unmodified active ingredient:

  • increased drug solubility
  • Extension of the periods between the application of the active ingredient without reducing the efficiency and usually with fewer toxic side effects
  • longer residence time in the patient's body, i.e. a larger area under the curve
  • increased drug stability
  • better protection against degradation by proteases

Commercially, PEGylation also has advantages. In addition to the development of more patient-friendly dosage forms and dosages, the patent terms of older active substance patents can also be extended through new patents.

PEGylated pharmaceuticals

The clinical benefit of PEGylation is widely recognized. Adagen , a PEGylated bovine adenosine deaminase (ADAR = Adenosine Deaminase Acting on RNA) manufactured by Enzon Pharmaceuticals Inc. (USA), was the first PEGylated protein to be approved by the FDA in March 1990 . Since Adagen was launched , a number of PEGylated proteins and peptides have received regulatory approvals and a large number are in clinical trials or development. Some selected examples:

The PEGylation

The first step in PEGylation is the functionalization of the polyethylene glycol molecule at both ends. Polyethylene glycols that are activated with the same functional group at both ends of the molecule are called “homobifunctional”. Functionalization with different functional groups is called “heterobifunctional” or “heterofunctional”. The functional groups are activated in such a way that they chemically bind the PEG to the desired target molecule.

The choice of functional groups at the ends of the PEG depends on which reactive groups the target molecule to which the PEG is to be coupled has. In the case of proteins, the typical binding sites are the reactive amino acids lysine , cysteine , histidine , arginine , aspartic acid , glutamic acid , serine , threonine , tyrosine , that is to say essentially terminal amino or carboxy groups .

The technology of the first generation of PEGylation generally used compounds that react with the hydroxyl groups of the PEG, such as carboxylic acid anhydrides or carboxylic acid chlorides . In the second generation of PEGylation chemistry, more powerful functional groups such as aldehydes or esters are used for conjugation with the corresponding biomolecule.

Due to the further development and spread of PEGylation, the need for heterobifunctional PEGs for conjugation has increased. These PEGs are very useful for joining two entities together when a hydrophilic biocompatible spacer is needed. Preferred end groups are maleimides , vinyl sulfonates, amines , carboxy groups and NHS esters .

Tracking the bioavailability of the PEGylated active ingredient is based on the immunochemical detection of the polyethylene glycol, more precisely the terminal methoxy group , because antibodies hardly recognize the PEGylated molecule itself.

Bibliography

  • Abuchowski, McCoy, Palczuk, van Es and Davis: Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. In: J Biol Chem 252/1977, pp. 3582-6, PMID 16907 (free full text).
  • Conan Fee: Size-exclusion reaction chromatography (SERC): A new technique for protein PEGylation. In: Biotechnology and Bioengineering 82/2003, pp. 200-6.
  • Fee, Alstine: PEG-proteins: Reaction engineering and separation issues. In: Chemical Engineering Science 61/2006, pp. 924-39, doi: 10.1016 / j.ces.2005.04.040 .
  • Kodera, Matsushima et al .: Pegylation of proteins and bioactive substances for medical and technical applications. In: Progress in Polymer Science 23/1998, pp. 1233-71, doi: 10.1016 / S0079-6700 (97) 00033-6 .
  • Morar et al .: PEGylation of Proteins: A Structural Approach. In: Biopharm International 19/2006, p. 34 ( online , free full text).
  • Roberts et al: Chemistry for peptide and protein PEGylation. In: Advanced Drug Delivery Reviews 54/2002, pp. 459-76, PMID 12052709 .
  • Veronese: Peptide and protein PEGylation: a review of problems and solutions. In: Biomaterials 22/2001, pp. 405-17, PMID 11214751 .
  • Veronese, Harris: Introduction and overview of peptide and protein pegylation. In: Advanced Drug Delivery Reviews 54/2002, pp. 453-6, PMID 12052707 .
  • Veronese, Pasut: PEGylation, successful approach to drug delivery. In: Drug Discovery Today 10/2005, pp. 1451-8, doi: 10.1016 / S1359-6446 (05) 03575-0 , PMID 16243265 .

Individual evidence

  1. ↑ PEGylation (English). Celares.com, accessed July 9, 2013.
  2. ^ Gianfranco Pasut, Francesco M. Veronese: PEGylation, successful approach to drug delivery. Drug Discovery Today, Vol. 10, Iss. 21, Nov. 1, 2005, pp. 1451-1458; doi: 10.1016 / S1359-6446 (05) 03575-0
  3. ↑ Pegasys from Roche, a pegylated interferon ( Memento from December 4, 2008 in the Internet Archive )
  4. ↑ Sensitive Detection of PEG-ylated Biopharmaceuticals with Anti-PEG RabMAb. ( Memento from July 22, 2012 in the web archive archive.today ) Biomol.de, accessed on August 31, 2011.
  5. ↑ Anti-PEG web portal