Stable antibody breakthrough solves sticky biotech problem

Antibodies are a popular vehicle for experimental therapeutics. However, they are also difficult to handle and are prone to sticking together – or “aggregating” – when isolated into an injectable form.

Now researchers from Sydney’s Garvan Institute and the University of New South Wales have developed a technique to produce superior antibodies that are more stable, robust and which resist the aggregation problem plaguing conventional antibodies.

These antibodies could prove a boon to biopharma companies exploring new therapies, allowing them to produce antibodies that are stable enough to meet the stringent requirements set by industry regulators for antibodies that are safely injectable and can be stored for long periods of time.

“When we talk to collaborators in industry, we find that 30-50 per cent of the antibody-based drugs they develop have to be put on hold because they don’t meet quality tests that the companies or regulatory agencies such as the US Food and Drug Administration, require before marketing or approving these molecules,” said co-author Dr Daniel Christ, from the University of New South Wales.

“Until now, the issue of antibody instability has been tackled on a case-by-case basis, which is only tinkering with the problem. When you’re dealing with such a diverse population of molecules, you have to make sure that the method you develop is generally applicable – and that’s what we’ve done.”

The researchers carefully modified various binding sites on the antibodies, thus lending them superior biophysical properties, such as minimising aggregating and making them heat-refoldable.

These modifications also didn’t interfere with variations in other regions of the antibodies, meaning they antibodies could still be modified as usual to produce specific therapeutic outcomes.

“Our challenge was to maintain biological activity under very unnatural conditions, for which antibodies were not optimised by evolution,” said Christ.

“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 will be to work with the pharmaceutical industry to improve the stability of antibody therapeutics for the treatment of cancer and inflammatory conditions.