06.09 Targeting therapeutic and regenerative biomedicine specifically to arthritic joints

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Abstract

Background

Systemic treatment with disease modifying anti-rheumatic drugs (DMARDs) is associated with side effects, since such treatment does not deliver pharmacologically active molecules solely to the site of disease activity in the joints

Background

We demonstrated 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). Our goal is to establish that antibodies specific to ROS-modified CII can be used to target therapeutics specifically to arthritic joints.

Methods

We raised antibodies specific to ROS-modified CII by phage display and validated the specificity by ELISA and immunostaining of articular cartilage from RA and OA patients. The in vivo targeting potential was tested by imaging using mice model with inflammatory arthritis and. The therapeutic effect of anti–ROS-CII was tested by fusing it to soluble murine tumour necrosis factor receptor II–Fc fusion protein (mTNFRII-Fc) and viral IL-10 (vIL-10).

Results

Anti-ROS-CII: i) binds specifically to arthritic cartilage from patients with RA and OA; ii) stains cartilage in murine models of inflammatory arthritis and OA; and iii) localises in the inflamed joint in vivo in a mouse model of antigen induced arthritis (AIA) following systemic administration of labelled anti-ROS-CII.

Results

Targeting mTNFR2-Fc or viral IL-10 significantly enhanced therapeutic effect on inflamed knee swelling in mouse model of inflammatory arthritis compared to un-targeted mTNFR2-Fc or viral IL-10 when they were fused to non-relevant antibody.

Results

We next developed a novel imaging platform whereby anti-ROS-CII labelled with Cy5.5 (a near-infrared (NIR) fluorescent probe) allowed us to successfully visualise development and progression of murine OA induced by destabilising of medial meniscus (DMM). Specific retention of Cy5.5-anti-ROS-CII scFv in the DMM joint was noted as early as 4 weeks post-surgery and before any evident cartilage damage.

Conclusion

The anti-ROS-CII antibodies have the potencial to become a very early diagnostic biomarker for OA as well as for targeting payload drug specifically to arthritic joints whether RA or OA.

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