In vivo optical imaging of early osteoarthritis using an antibody specific to damaged arthritic cartilage

Osteoarthritis (OA) is a disease of the whole joint with articular cartilage breakdown
as a major characteristic, but also involving pathology within the synovium, bone,
menisci, ligaments, muscles and neural tissues 1], 2]. OA is the most common joint disease, with a population-wide prevalence of symptomatic
disease of approximately 15 %, 12 % and 6 % in the hand, knee and hip, respectively
3]. Ageing of the world’s population is likely to increase the burden of this disease
further 4].

Given the huge economic and personal burden of OA, there is an urgent unmet need to
develop disease-modifying OA drugs (DMOADs) that can reduce or stop its progression.
Treatment with drugs such as non-steroidal 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]. The introduction of potential DMOADs, however, has been hampered by the lack of
specific and sensitive biomarkers capable of detecting early disease or discerning
modest changes in disease progression. Much funding has gone into the search for novel
serum, urine and synovial fluid biomarkers of disease progression, but thus far no
single soluble biomarker has been shown to have value either in disease severity prediction
or progression within an individual 6], 7]. Of these markers, only serum cartilage oligomeric protein levels maintained association
with OA in large-scale studies with a low odds ratio of 3.26 8].

The current gold standard for disease evaluation, in spite of its limitations, is
the plain radiograph, which relies on the presence of relatively late features of
the disease, including presence of osteophytes, joint space narrowing (signifying
marked cartilage loss) and bone remodeling 9]. X-ray images are insensitive to early changes within the joint and do not report
on cartilage or synovial pathology as these soft tissues are transparent to X-rays.
Although magnetic resonance imaging (MRI) is a more sensitive and specific radiographic
tool for assessment of OA joint changes (including cartilage loss, synovitis, bone
oedema, etc.) 9], its widespread use in clinical practice is hampered by cost, long acquisition times
and poor patient acceptability 10]. MRI is, however, becoming a key imaging tool for OA research 9], 11]–15] due to its ability to detect changes at pre-radiographic OA 9], 16]. Another drawback of MRI is that the significance of many MRI features in pre-radiographic
OA are still unclear and therefore of limited clinical utility 17].

Biochemical markers in combination or used in conjunction with imaging may prove to
be more powerful in establishing stage of disease, predicting progression, and assessing
improvement in clinical trials 18]. Potential DMOADs need to be first validated in preclinical studies mostly utilizing
small animal models of OA 3], 19], 20]. Currently, disease is assessed by serial histology of the joint which is time consuming,
costly and requires large number of animals as they need to be culled at each experimental
time point under investigation. Powerful non-invasive preclinical imaging techniques
for longitudinal studies are therefore highly desirable for preclinical validation
studies as well as for detection and monitoring of early OA in patients.

We have developed a panel of human single chain fragment variables (scFvs) 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]. One scFv candidate, namely 1-11E, binds specifically to arthritic cartilage from
human OA and rheumatoid arthritis, as well as experimental OA and inflammatory arthritis,
but not to healthy cartilage 21], 22]. Hence, 1-11E targeted a payload drug to arthritic joints following systemic administration
in inflammatory mouse model of arthritis 21], 22]. Here, we assess the utility of Cy5.5-labelled 1-11E-scFv and monoclonal antibody
(mAb) as an imaging probe to detect early disease in mice with experimental OA induced
by destabilisation of the medial meniscus (DMM).