Updated on 29 June 2012
Antibodies have ‘constant regions' and ‘variable regions', the latter determining the binding specificity of the molecule. The shape of the variable region will exactly match the ‘antigen', or invader, in the same way as a lock matches a key.
With infinite variability of antibody structure comes varying levels of stability. It is fairly common, therefore, to have an antibody that is very good at binding to a specific antigen, but which is also very unstable. The mutations created by the Garvan team fix the stability problem without compromising the antigen binding properties of an antibody. Antibodies consist of two chains - a heavy and a light chain - and Dr Christ emphasises that mutations have to work with each chain individually and both chains in combination.
"Typically you'd have both chains present in a therapeutic molecule, as well as additional biological activity, such as the ability to bind to a cancer target," he said.
"Our challenge was to maintain biological activity under very unnatural conditions, for which antibodies were not optimised by evolution. It is really when you take these molecules out of their natural environment, purify and concentrate them, that stresses become apparent. When used as a drug, antibodies are formulated at very high concentrations, for instance for delivery in a small syringe. You end up with an almost honey-like, highly viscous preparation. Under these conditions, antibodies can stick to surfaces like tubing and become entangled with one another. Our mutations make them much less sticky, much less entangled. They also make the antibodies more robust against common storage methods such as freeze drying."
The next step for the Garvan team will be to work with colleagues in the pharmaceutical industry to improve the stability of antibody therapeutics for the treatment of cancer and inflammatory conditions.