%0 Journal Article %1 thomas2023design %A Thomas, S. %A Fiebig, J. E. %A Kuhn, E. M. %A Mayer, D. S. %A Filbeck, S. %A Schmitz, W. %A Krischke, M. %A Gropp, R. %A Mueller, T. D. %D 2023 %J ACS Omega %K imported myOwn uni_network %N 28 %P 24841-24852 %R 10.1021/acsomega.3c00726 %T Design of Glycoengineered IL-4 Antagonists Employing Chemical and Biosynthetic Glycosylation %U https://www.ncbi.nlm.nih.gov/pubmed/37483220https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10357448/pdf/ao3c00726.pdf %V 8 %X Interleukin-4 (IL-4) plays a key role in atopic diseases. It coordinates T-helper cell differentiation to subtype 2, thereby directing defense toward humoral immunity. Together with Interleukin-13, IL-4 further induces immunoglobulin class switch to IgE. Antibodies of this type activate mast cells and basophilic and eosinophilic granulocytes, which release pro-inflammatory mediators accounting for the typical symptoms of atopic diseases. IL-4 and IL-13 are thus major targets for pharmaceutical intervention strategies to treat atopic diseases. Besides neutralizing antibodies against IL-4, IL-13, or its receptors, IL-4 antagonists can present valuable alternatives. Pitrakinra, an Escherichia coli-derived IL-4 antagonist, has been evaluated in clinical trials for asthma treatment in the past; however, deficits such as short serum lifetime and potential immunogenicity among others stopped further development. To overcome such deficits, PEGylation of therapeutically important proteins has been used to increase the lifetime and proteolytic stability. As an alternative, glycoengineering is an emerging strategy used to improve pharmacokinetics of protein therapeutics. In this study, we have established different strategies to attach glycan moieties to defined positions in IL-4. Different chemical attachment strategies employing thiol chemistry were used to attach a glucose molecule at amino acid position 121, thereby converting IL-4 into a highly effective antagonist. To enhance the proteolytic stability of this IL-4 antagonist, additional glycan structures were introduced by glycoengineering utilizing eucaryotic expression. IL-4 antagonists with a combination of chemical and biosynthetic glycoengineering could be useful as therapeutic alternatives to IL-4 neutralizing antibodies already used to treat atopic diseases.

@article{thomas2023design, abstract = {Interleukin-4 (IL-4) plays a key role in atopic diseases. It coordinates T-helper cell differentiation to subtype 2, thereby directing defense toward humoral immunity. Together with Interleukin-13, IL-4 further induces immunoglobulin class switch to IgE. Antibodies of this type activate mast cells and basophilic and eosinophilic granulocytes, which release pro-inflammatory mediators accounting for the typical symptoms of atopic diseases. IL-4 and IL-13 are thus major targets for pharmaceutical intervention strategies to treat atopic diseases. Besides neutralizing antibodies against IL-4, IL-13, or its receptors, IL-4 antagonists can present valuable alternatives. Pitrakinra, an Escherichia coli-derived IL-4 antagonist, has been evaluated in clinical trials for asthma treatment in the past; however, deficits such as short serum lifetime and potential immunogenicity among others stopped further development. To overcome such deficits, PEGylation of therapeutically important proteins has been used to increase the lifetime and proteolytic stability. As an alternative, glycoengineering is an emerging strategy used to improve pharmacokinetics of protein therapeutics. In this study, we have established different strategies to attach glycan moieties to defined positions in IL-4. Different chemical attachment strategies employing thiol chemistry were used to attach a glucose molecule at amino acid position 121, thereby converting IL-4 into a highly effective antagonist. To enhance the proteolytic stability of this IL-4 antagonist, additional glycan structures were introduced by glycoengineering utilizing eucaryotic expression. IL-4 antagonists with a combination of chemical and biosynthetic glycoengineering could be useful as therapeutic alternatives to IL-4 neutralizing antibodies already used to treat atopic diseases.}, added-at = {2024-02-15T15:08:22.000+0100}, author = {Thomas, S. and Fiebig, J. E. and Kuhn, E. M. and Mayer, D. S. and Filbeck, S. and Schmitz, W. and Krischke, M. and Gropp, R. and Mueller, T. D.}, biburl = {https://www.bibsonomy.org/bibtex/22abe260bcf40a1be88fad2d22d057b4e/jvsi_all}, doi = {10.1021/acsomega.3c00726}, interhash = {3745b7f0fe73cb3d92027dbc240c1313}, intrahash = {2abe260bcf40a1be88fad2d22d057b4e}, issn = {2470-1343 (Electronic) 2470-1343 (Linking)}, journal = {ACS Omega}, keywords = {imported myOwn uni_network}, note = {Thomas, Sarah Fiebig, Juliane E Kuhn, Eva-Maria Mayer, Dominik S Filbeck, Sebastian Schmitz, Werner Krischke, Markus Gropp, Roswitha Mueller, Thomas D eng 2023/07/24 ACS Omega. 2023 Jul 5;8(28):24841-24852. doi: 10.1021/acsomega.3c00726. eCollection 2023 Jul 18.}, number = 28, pages = {24841-24852}, timestamp = {2024-02-15T15:11:55.000+0100}, title = {Design of Glycoengineered IL-4 Antagonists Employing Chemical and Biosynthetic Glycosylation}, type = {Journal Article}, url = {https://www.ncbi.nlm.nih.gov/pubmed/37483220https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10357448/pdf/ao3c00726.pdf}, volume = 8, year = 2023 }