%0 Journal Article %1 spieler2020targeting %A Spieler, V. %A Ludwig, M. G. %A Dawson, J. %A Tigani, B. %A Littlewood-Evans, A. %A Safina, C. %A Ebersbach, H. %A Seuwen, K. %A Raschig, M. %A Ter Mors, B. %A Muller, T. D. %A Meinel, L. %A Luhmann, T. %D 2020 %J J Control Release %K Acids Amino myOwn uni_network %P 172-180 %R 10.1016/j.jconrel.2020.07.005 %T Targeting interleukin-4 to the arthritic joint %U https://www.ncbi.nlm.nih.gov/pubmed/32653504 %V 326 %X Anti-inflammatory cytokines are a promising class of therapeutics for treatment of rheumatoid arthritis (RA), but their use is currently limited by a rapid clearance and systemic toxicity. Interleukin-4 is a small cytokine with potential for RA therapy. To increase its pharmacokinetic features, we engineered a murine IL4 conjugate by incorporating an unnatural amino acid through genetic code expansion to which PEG-folate, as a targeting moiety and PEG alone as control, were site-specifically bound. Both IL4 conjugates retained bioactivity and induced primary murine macrophage polarization into an alternatively activated (M2) related phenotype. The PEGylated conjugates had a terminal half-life of about four hours in healthy mice compared to unPEGylated IL4 (0.76 h). We showed that both conjugates successfully accumulated into arthritic joints in an antigen-induced arthritis (AIA) mouse model, as assessed by non-invasive fluorescence imaging. The modular nature of the IL4 conjugate chemistry presented herein facilitates easy adaption of PEG chain length and targeting moieties for further improvement of half-life and targeting function for future efficacy studies.

@article{spieler2020targeting, abstract = {Anti-inflammatory cytokines are a promising class of therapeutics for treatment of rheumatoid arthritis (RA), but their use is currently limited by a rapid clearance and systemic toxicity. Interleukin-4 is a small cytokine with potential for RA therapy. To increase its pharmacokinetic features, we engineered a murine IL4 conjugate by incorporating an unnatural amino acid through genetic code expansion to which PEG-folate, as a targeting moiety and PEG alone as control, were site-specifically bound. Both IL4 conjugates retained bioactivity and induced primary murine macrophage polarization into an alternatively activated (M2) related phenotype. The PEGylated conjugates had a terminal half-life of about four hours in healthy mice compared to unPEGylated IL4 (0.76 h). We showed that both conjugates successfully accumulated into arthritic joints in an antigen-induced arthritis (AIA) mouse model, as assessed by non-invasive fluorescence imaging. The modular nature of the IL4 conjugate chemistry presented herein facilitates easy adaption of PEG chain length and targeting moieties for further improvement of half-life and targeting function for future efficacy studies.}, added-at = {2024-02-15T15:11:54.000+0100}, author = {Spieler, V. and Ludwig, M. G. and Dawson, J. and Tigani, B. and Littlewood-Evans, A. and Safina, C. and Ebersbach, H. and Seuwen, K. and Raschig, M. and Ter Mors, B. and Muller, T. D. and Meinel, L. and Luhmann, T.}, biburl = {https://www.bibsonomy.org/bibtex/27b163b1ac0c6a2ae1add13fe344599ea/jvsi_all}, doi = {10.1016/j.jconrel.2020.07.005}, interhash = {450ccb32ca58733e2036d429edb8aa1e}, intrahash = {7b163b1ac0c6a2ae1add13fe344599ea}, issn = {1873-4995 (Electronic) 0168-3659 (Linking)}, journal = {J Control Release}, keywords = {Acids Amino myOwn uni_network}, note = {Spieler, Valerie Ludwig, Marie-Gabrielle Dawson, Janet Tigani, Bruno Littlewood-Evans, Amanda Safina, Caterina Ebersbach, Hilmar Seuwen, Klaus Raschig, Martina Ter Mors, Bjorn Muller, Thomas D Meinel, Lorenz Luhmann, Tessa eng Research Support, Non-U.S. Gov't Netherlands 2020/07/13 J Control Release. 2020 Oct 10;326:172-180. doi: 10.1016/j.jconrel.2020.07.005. Epub 2020 Jul 10.}, pages = {172-180}, timestamp = {2024-02-15T15:11:54.000+0100}, title = {Targeting interleukin-4 to the arthritic joint}, type = {Journal Article}, url = {https://www.ncbi.nlm.nih.gov/pubmed/32653504}, volume = 326, year = 2020 }