Characterisation of scFv A7 reactivity and development of a novel bispecific antibody for targeted therapies in Rheumatoid Arthritis.
Abstract
Despite the success of current biological agents, achievement of broader
efficacy and improved safety profile remains an unmet need in rheumatoid arthritis
therapy. Neovasculogenesis plays a vital role in the progression and perpetuation of
rheumatoid arthritis and significant evidence has demonstrated molecular
heterogeneity within the endothelium (MVE) of different tissues. The heterogeneity
of the synovial MVE can be exploited for the development of organ-specific
therapeutic and diagnostic reagents. A novel recombinant antibody fragment, scFv
A7, with specificity for human arthritic synovium, was isolated in our laboratory
following in vivo phage display. The aim of the project described in this thesis is to
characterise the antibody reactivity and develop a novel tissue specific therapeutic.
The scFv A7 antibody proved to specifically target the microvasculature of
human arthritic synovium with no detectable reactivity in a comprehensive range of
normal tissues. Furthermore, the detected reactivity was not a common feature of
chronic inflammatory conditions. Hence, the A7 antibody represents a unique and
versatile tool with great potential for the development of diagnostic and/or
therapeutic agents.
The unique properties of A7 were combined with the anti-TNF Adalimumab,
forming a bispecific antibody with neutralising activity and synovial homing
properties. The new construct was able to retain the synovial specificity and
showed comparable TNF binding kinetics and biological activity to the parent
Adalimumab antibody in vitro.
In conclusion, these results demonstrate that scFv A7 reactivity is specific to
the microvasculature of human arthritic synovium, suggesting that the target
molecule may have potential as a biomarker in arthritis and applications as an
immunotherapeutic target. The bispecific antibody format developed showed
unaltered TNF blocking capacity and synovial specificity that may allow reduction in
the dosage and/or administration frequency, with the ultimate goal to reduce the
systemic exposure, achieve a better therapeutic index and decreasing health care
costs.
Authors
Ferrari, MathieuCollections
- Theses [4490]