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Addressing Practical Issues in Atomic Force Microscopy-Based Micro-Indentation on Human Articular Cartilage Explants
Published on: October 28, 2022
Human single-chain variable fragment that specifically targets arthritic cartilage
Chris Hughes1, Bjarne Faurholm, Francesco Dell'Accio
1Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
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.
Insights
Researchers developed antibodies targeting reactive oxygen species-modified type II collagen (ROS-CII) found in damaged cartilage. These antibodies successfully targeted inflamed arthritic joints in mice, reducing inflammation and showing potential for arthritis therapeutics.
Area of Science:
- Biochemistry and Molecular Biology
- Immunology
- Rheumatology
Background:
- Reactive oxygen species (ROS) are present in inflamed arthritic joints.
- ROS can modify type II collagen (CII), creating unique epitopes.
- These modified epitopes are specific to damaged cartilage in rheumatoid arthritis (RA) and osteoarthritis (OA).
Purpose of the Study:
- To demonstrate that ROS-modified CII generates epitopes specific to damaged arthritic cartilage.
- To establish antibodies targeting ROS-modified CII as a proof of concept for targeted therapeutics.
- To assess the potential of these antibodies for specifically targeting inflamed arthritic joints.
Main Methods:
- A phage display human antibody library was used to generate single-chain variable fragments (scFv) against ROS-modified CII.
- Specificity was assessed in vitro using immunostaining of human arthritic and normal cartilage.
- In vivo targeting was evaluated in mice with antigen-induced arthritis, assessing joint localization and therapeutic effects of fused antibodies.
Main Results:
- Anti-ROS-modified CII scFv selectively bound to damaged cartilage from RA and OA patients, not normal cartilage.
- Systemic administration of anti-ROS-modified CII scFv led to selective accumulation in inflamed joints of arthritic mice.
- Fusion of anti-ROS-modified CII scFv to mTNFRII-Fc significantly reduced joint inflammation in mice.
Conclusions:
- Biologic therapeutics can be effectively targeted to arthritic joints using antibodies against ROS-modified CII.
- This approach offers a novel strategy for developing targeted treatments for arthritis.
- Targeting ROS-modified CII represents a promising new avenue for arthritis therapy.