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Title: Targeting microvesicles to the arthritic joint using antibodies specific to damaged cartilage
Author: Topping, Louise
ISNI:       0000 0004 7971 8209
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2019
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Rheumatoid arthritis (RA) is a systemic autoimmune disease and the second most common form of arthritis. The efficacy of current treatments for RA is limited by an increased risk of off target effects and a high percentage of non-responders. To try and overcome this, human antibodies that bind specifically to damaged arthritic cartilage, but not healthy cartilage, were developed for means of delivering drugs to the joints. The antibodies are specific to collagen type II (CII), the major cartilage protein, that has been post-translationally modified by reactive oxidants (ROS, resulting in ROS-CII), which is abundantly found in inflamed joints. It has previously been shown that fusing anti-ROS-CII antibodies to either a mouse version of etanercept or viral-IL-10 significantly enhanced the therapeutic effect on the inflamed knee in a mouse model of arthritis. Herein, a new treatment modality was created to attempt to utilise the anti-ROS-CII antibodies to target biological scaffolds to the arthritic joint. As a biological scaffold, microvesicles (MV), a subset of extracellular vesicles released from the plasma membrane of nearly all cells, were utilised. Specifically, MV derived from neutrophils (PMN) were used. MV from PMN have been previously shown to penetrate cartilage and exert chondro-protective effects in the context of inflammatory arthritis. Antibodies specific to ROS-CII retained their binding capabilities after enrichment upon MV, and anti-ROS-CII enriched MV exhibited the ability to localise specifically in the arthritic joint in vivo. The targeted MV were then co-loaded with anti-inflammatory therapeutics to deliver a pro-resolving 'magic bullet' to the arthritic knee in vivo. Importantly, targeting MV with anti-ROS-CII alongside combined treatments led to the complete amelioration of knee inflammation. Overall, this study demonstrates the attainability of targeting a pro-resolving biological scaffold to the arthritic joint. The potential of co-delivering MV alongside anti-inflammatory therapeutics is beneficial to simultaneously protect cartilage and reduce inflammation.
Supervisor: Not available Sponsor: QMUL Life Sciences Initiative
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Rheumatoid arthritis ; Damaged Cartilage ; Arthritic Joint ; Microvesicles