Targeting interleukin-4 to the arthritic joint

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 molecular weight 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 codon expansion to which PEG-folate as targeting moiety and PEG 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. 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 to further improvement of half-life and targeting function for future efficacy studies