Glycosylation of therapeutic proteins in different production systems

  • Werner R
  • Kopp K
  • Schlueter M
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Abstract

Glycosylation plays an important role in a number of therapeutic proteins, including monoclonal antibodies. The enzymatic activity of a therapeutic protein is mainly determined by the protein structure, whereas the pharmacokinetics, pharmacodistribution, solubility, stability, enhancement of effector function and receptor binding are all influenced by the carbohydrate moiety. Hyperglycosylated proteins show increased serum half-life, are less sensitive to proteolysis and more heat-stable compared with the non-glycosylated forms. Molecular engineering of the TNK-tissue plasminogen activator molecule results in a more complex type of glycosylation and increases the half-life of the protein, which allows a single bolus injection at a lower dose for the treatment of acute myocardial infarction. Antibody-dependent cell cytotoxicity (ADCC) is determined partially by the specific N-glycosylation of the Fc domain of the monoclonal antibody. Specific glycoforms of monoclonal antibodies, which interact solely with the FcgammaRIIIa receptor of natural killer cells, result in superior ADCC compared with heterogeneous glycoforms that interact with different Fc receptors. This demonstrates that glycoengineering for directed glycosylation of therapeutic proteins can improve the therapeutic effect. While the amino acid sequence of the therapeutic protein is determined by the nucleotide sequence of the inserted gene, glycosylation depends on the glycosylating enzymes in the endoplasmatic reticulum and the Golgi apparatus of the eukaryotic host cell. In addition, the glycosylation of the therapeutic protein is affected by the culture medium used, the efficiency of protein expression and the physiological status of the host cell. CONCLUSION: For a given protein, changes in the type of host cell, composition of the culture media and fermentation conditions during process development will most likely result in changes in the site occupation and heterogeneity of glycosylation. This, of course, can influence the therapeutic profile. Therefore, the early selection of the host cell and selection of upstream parameters are key in the process development of a product

Author-supplied keywords

  • Amino Acid Sequence
  • Animals
  • Antibodies
  • Antibodies,Monoclonal
  • Cells
  • Chemistry,Pharmaceutical
  • Cho Cells
  • Cricetinae
  • Cricetulus
  • Culture Media
  • Enzymes
  • Glycoproteins
  • Glycosylation
  • Golgi Apparatus
  • Half-Life
  • Humans
  • Myocardial Infarction
  • Plasminogen
  • Protein Processing,Post-Translational
  • Proteins
  • Solubility
  • metabolism
  • pharmacokinetics
  • physiology

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  • PMID: 17391433

Authors

  • R G Werner

  • K Kopp

  • M Schlueter

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