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.
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.
%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
}