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Assessment of novel therapeutics and development of monoclonal antibody targeting moieties for drug delivery systems in the treatment of osteoarthritis

Whitehead, Bradley 2019. Assessment of novel therapeutics and development of monoclonal antibody targeting moieties for drug delivery systems in the treatment of osteoarthritis. PhD Thesis, Cardiff University.
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In Part 1 of this work ex vivo models of cytokine induced cartilage degradation were developed and extensively characterised for the subsequent assessment of Surfen, a heparan sulphate antagonist as a potential therapeutic for the treatment of osteoarthritis (OA). Cell signalling pathway analysis revealed synergistic activation of the stress-activated protein kinase (SAPK/JNK) pathway mediated by interleukin-1 alpha (IL-1a) + Oncostatin M (OSM) compared to either cytokine alone. Pharmacological inhibition confirmed the role of SAPK/JNK in catabolic gene expression and cartilage matrix degradation. Analysis of cartilage oligomeric matrix degradation (COMP) in cartilage in response to cytokines identified a role for ADAMTS-4 in COMP degradation. Surfen is a known inhibitor of anthrax lethal factor metalloproteinase. This Thesis identified Surfen as a direct inhibitor of ADAMTS-4 and furin, a pro-protein convertase involved in ADAMTS activation. Surfen inhibited glycosaminoglycan (GAG) loss and aggrecanase activity in IL-1a but not IL-1a+OSM treated cartilage explants. Gene expression studies showed Surfen (7 μM) attenuated IL-1a and IL-1a+OSM mediated increases in catabolic gene expression, however, increased Surfen concentration (15 μM) resulted in increased ADAMTS-4 expression and activity in IL-1a+OSM conditions that likely precludes the use of Surfen as an OA therapy. Targeting of sustained release drug delivery systems (DDS) to specific tissues within the joint could increase retention whilst reducing off-target effects. In Part 2 lubricin was identified as a candidate cartilage surface target. Conjugation of anti-lubricin mAb to DDS improved binding and retention in ex vivo studies. For the targeting of pro-inflammatory M1 subtype macrophages in the synovium, novel mAbs were developed to target human and murine FcgRI/CD64. Assessment of mIgG1 and mIgG2a anti-FcgRI/CD64 binding revealed species and isotype specific differences in non-specific binding to monocyte cell lines, whereas no non-specifc binding of mIgM was observed suggesting in these subtypes are preferential in the specifc targeting of FcgRI/CD64. Combined, this Thesis has assesed the potential of a novel therapeutic and developed novel joint targeting strategies for treatment of OA.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Date of First Compliant Deposit: 11 September 2019
Last Modified: 11 Sep 2019 16:05

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