Scientists have developed a new technique for purifying proteins during antibody manufacturing. The aim is to reduce the cost of continuous manufacturing for large-scale applications, such as COVID-19 therapeutics or Alzheimer’s disease treatments, without the need for Protein A.

“Protein A chromatography is robust and works well, but it’s also expensive and can create significant supply chain problems because you have to produce the Protein A and immobilize it on a resin,” says Andrew Zydney, PhD, professor of chemical engineering at Pennsylvania State University. “Our hope is that, by moving away from Protein A, we open up opportunities that are higher throughput and lower cost.”

His research, which was presented recently at PepTalk 2021, uses precipitation—an old technique for protein purification during downstream bioprocessing. According to Zydney, precipitation technology is more than fifty years old, but was not suitable for purifying recombinant proteins until recently.

“When recombinant proteins were originally developed, the titers from bioreactors were so low that precipitation was not an option,” he explains. “But there’s been so much progress in the last twenty years improving upstream performance for antibody production, that precipitation is attractive again.”

Zydney’s new technique uses a hollow fiber membrane, shaped like a tube, as a filter. As a protein precipitate flows through the hollow fiber, unwanted host cell proteins and media pass through the sides of the tube and can be removed. Flowing the precipitate through a filter tube prevents the filter from getting clogged, which means the filtration process can run continuously without cleaning, he explains. Moreover, using a precipitate removes the need for Protein A.

“When you have large requirements for monoclonals, such as for COVID-19 therapeutics, it’s not clear that Protein A is a viable strategy for making antibodies in a cost-effect manner,” he says.

The research was carried out using monoclonal antibodies, in partnership with Rensselaer Polytechnic Institute (RPI), and Boehringer Ingelheim. However, Zydney believes the technique can be used for any recombinant protein produced at relatively high concentration.

The team is now looking to improve their technique by reducing fouling of the filter and by improving the flow and filtration properties of the protein precipitate.

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