Evaluation of a novel biomarker as a predictor of response, stratification tool, and measure of pharmacology for a disease-modifying osteoarthritis therapeutic

Thesis

Introduction

Osteoarthritis (OA) is a leading cause of disability in developed countries and is independently associated with increased mortality. Aggrecan degradation is an early process in OA-related cartilage degradation, principally attributed to activity of the aggrecanase ADAMTS-5. One of the products of this activity is ARGS neoepitope which is proposed as a biomarker of OA disease burden. Biomarker measurement and correlation could advance research into effective intervention in OA. In this study we aim to assess ARGS neoepitope as a marker of OA disease burden through correlation with MRI-derived imaging outcome measures. We also assess an ADAMTS5-specific monoclonal antibody for its viability as an OA pharmaceutical intervention.

Methodology

This study is a cross-sectional cohort study of 95 knee surgical patients to measure ARGS neoepitope using electrochemiluminescent assay on serum, urine and synovial fluid. Specific software was used to generate MRI-derived outcome measures such as volume and intensity measures, allowing comparison of these two outcome measures. This study also investigated ARGS neoepitope response to an ADAMTS-5 blocking monoclonal antibody in vitro in a human explant model.

Results

A significantly higher level of ARGS neoepitope was found in urine samples (1.58-fold, P = 0.006) of patients with late compared to early disease, whilst no significant differences in neoepitope values were detected in synovial fluid and serum samples. With regard to disease burden, ARGS neoepitope was correlated with medial compartment cartilage loss in medial unicompartmental knee replacement patients (R² = 0.249; P = 0.012) however in general it was not strongly related to imaging markers. In the in vitro work the ADAMTS-5 specific monoclonal antibody produced a dose-dependent reduction in ARGS neoepitope released from cartilage explants. Compared to the isotype control the mean reduction of ARGS neoepitope at 12 days was 43.6% (P < 0.001).

Discussion

The relationship between serological biomarkers of OA and disease burden remains complex. ARGS neoepitope may reflect enzymatic turnover of cartilage within the joint but the relationship with OA disease burden cannot be fully established by this study. Many factors including physical activity, disease status in other joints and patient muscle mass, could cause single time-point results to become less reliable and impact on the findings of both this and all OA biomarker studies.

Conclusion

This study demonstrates that ARGS neoepitope shows some promise as an OA biomarker and provides important information on conducting future studies assessing this and other biomarkers in OA.

Authors: Sprot, H

• DOI: 10.5287/ora-brx5z9g8d
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford