Human single-chain variable fragment that specifically targets arthritic cartilage

Chris Hughes, Bjarne Faurholm, Francesco Dell'Accio, Antonio Manzo, Michael Seed, Noha Eltawil, Alessandra Marrelli, David Gould, Christina Subang, Adam Al-Kashi, Cosimo De Bari, Paul Winyard, Yuti Chernajovsky, Ahuva Nissim

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Objective
To demonstrate that posttranslational modification of type II collagen (CII) by reactive oxygen species (ROS), which are known to be present in inflamed arthritic joints, can give rise to epitopes specific to damaged cartilage in rheumatoid arthritis (RA) and osteoarthritis (OA) and to establish a proof of concept that antibodies specific to ROS-modified CII can be used to target therapeutics specifically to inflamed arthritic joints.

Methods
We used a semisynthetic phage display human antibody library to raise single-chain variable fragments (scFv) specific to ROS-modified CII. The specificity of anti–ROS-modified CII scFv to damaged arthritic cartilage was assessed in vitro by immunostaining articular cartilage from RA and OA patients and from normal controls. The in vivo targeting potential was tested using mice with antigen-induced arthritis, in which localization of anti–ROS-modified CII scFv in the joints was determined. The therapeutic effect of anti–ROS-modified CII scFv fused to soluble murine tumor necrosis factor receptor II–Fc fusion protein (mTNFRII-Fc) was also investigated.

Results
The anti–ROS-modified CII scFv bound to damaged arthritic cartilage from patients with RA and OA but not to normal preserved cartilage. When systemically administered to arthritic mice, the anti–ROS-modified CII accumulated selectively at the inflamed joints. Importantly, when fused to mTNFRII-Fc, it significantly reduced inflammation in arthritic mice, as compared with the effects of mTNFRII-Fc alone or of mTNFRII-Fc fused to an irrelevant scFv.

Conclusion
Our findings indicate that biologic therapeutics can be targeted specifically to arthritic joints and suggest a new approach for the development of novel treatments of arthritis.
Original languageEnglish
Pages (from-to)1007-1016
Number of pages10
JournalArthritis & Rheumatism
Volume62
Issue number4
Early online date28 Jan 2010
DOIs
Publication statusPublished - Apr 2010

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    Hughes, C., Faurholm, B., Dell'Accio, F., Manzo, A., Seed, M., Eltawil, N., Marrelli, A., Gould, D., Subang, C., Al-Kashi, A., De Bari, C., Winyard, P., Chernajovsky, Y., & Nissim, A. (2010). Human single-chain variable fragment that specifically targets arthritic cartilage. Arthritis & Rheumatism, 62(4), 1007-1016. https://doi.org/10.1002/art.27346