Small antibodies with a big opportunity: The variable domain of the heavy chain only antibody and its potential as disease modifying osteoarthritic drug

Osteoarthritis (OA) is the most common joint disorder worldwide and its incidence is still increasing. It is a degenerative disease that is mainly characterized by progressive loss of articular cartilage, mild signs of synovial inflammation and typical changes in the bone. Currently, no curative treatment for OA exists which shows the need for not only lifestyle changes but also the development of therapeutics. In this thesis we discuss the potential of the variable domain of the heavy chain only antibody (VHH) as disease modifying OA drug. VHH are known for their small size, great stability and are easy to engineer. Altogether, this makes this specific type of antibody a suitable candidate for the local treatment of OA.
We show the potential of a VHH that targets interleukin-1 receptor with high affinity and show it can block interleukin-1 signaling, which is an important factor that drives inflammation. In addition, we show the ability of the VHH to be encapsulated within a drug delivery system and (bio)conjugated to to dextran tyramine and dextran/hyaluronic acid tyramine polymer and hydrogels. As a proof of concept, both strategies were tested in vivo to determine their retention time. Furthermore, we show characterization of a biparatopic VHH construct targeting two epitopes of interleukin-1 receptor. To conclude, we have made some steps towards a potential new disease modifying osteoarthritic drug.