Abstract
BackgroundThe lack of specific and sensitive serum and radiographic biomarkers for early diagnosis of osteoarthritis (OA) as well as for monitoring subtle changes in disease activity in clinical trials has hampered the development of treatments for OA. We previously showed that 1-11E, a human single chain fragment variable (scFv) specific to collagen type II that has been post-translationally modified by reactive oxidants (ROS-CII), binds exclusively to arthritic cartilage. Here we test the validity of 1-11E as a radiographic biomarker for early disease in experimental OA.MethodsMurine OA was induced by destabilisation of the medial meniscus (DMM) in adult male mice. Immunohistochemistry of destabilised or sham-operated knees was performed from 2 to 8 weeks post-surgery with Cy5.5-labelled 1-11E and negative control scFv, C7. Prospective in vivo optical images were taken 4 and 8 weeks post-DMM following intra-articular injection of Cy5.5-labelled scFvs, or intravenous injection of Cy5.5-labelled full length monoclonal antibodies (mAbs).ResultsSpecific cartilage staining with 1-11E was apparent as early as 4 weeks post-DMM at the time of earlier cartilage degradation assessed by histology. Prospective in vivo optical images taken 4 and 8 weeks post-DMM following local intra-articular injection of Cy5.5-labelled scFv (n = 7) showed specific in vivo retention of Cys5.5-1-11E scFv following local administration into the knee joint (tissue half-life >78 hours, n = 7, signal to noise ratio (SNR) > 2.1). Specific localization of Cys-5.5-1-11E-mAb to DMM knees (SNR >1.65) was also observed (p < 0.01, n = 8, SNR >1.65). In both cases the SNR increased with time post-DMM.Conclusions1-11E binds specifically to early osteoarthritic cartilage and can be used as a radiographic biomarker following local or systemic delivery to facilitate early diagnosis and monitor disease progression in OA.
Highlights
The lack of specific and sensitive serum and radiographic biomarkers for early diagnosis of osteoarthritis (OA) as well as for monitoring subtle changes in disease activity in clinical trials has hampered the development of treatments for OA
We have developed a panel of human single chain fragment variables specific for collagen type II that has been post-translationally modified by reactive oxidant species (ROS-CII), known to be present in the arthritic joint [21]
Immunohistochemical localisation of 1-11E in OA cartilage Joint sections were probed with the Cy5.5-1-11E-single chain fragment variable (scFv) or control Cy5.5-C7-scFv and visualised under the confocal microscope
Summary
The lack of specific and sensitive serum and radiographic biomarkers for early diagnosis of osteoarthritis (OA) as well as for monitoring subtle changes in disease activity in clinical trials has hampered the development of treatments for OA. Given the huge economic and personal burden of OA, there is an urgent unmet need to develop diseasemodifying OA drugs (DMOADs) that can reduce or stop its progression. Treatment with drugs such as nonsteroidal anti-inflammatory drugs, opioid-derived analgesic drugs or locally administered corticosteroids have moderate effects on symptomatic disease, but for many patients joint replacement surgery represents the only hope of relief [5]. Much funding has gone into the search for novel serum, urine and synovial fluid biomarkers of
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