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“Like turbocharging your car”: The future of personalized medicine could hinge on a microscopic process from Sweden

Making the biopharmaceuticals that treat the most devastating illnesses just got faster and easier

Chromatographic separation using Protein A is the most common first step to purifying monoclonal antibodies.

Every day, patients around the world rely on monoclonal antibody therapies to treat the most devastating illnesses, including cancer, Alzheimer’s and autoimmune diseases like multiple sclerosis and ulcerative colitis. These biopharmaceuticals were discovered decades ago, but they’ve seen dramatic growth in the last decade, as doctors search for new ways to treat their sickest patients and patients look for relief.

In an age of increasing personalized medicine, one form of immunotherapy relies almost entirely on monoclonal antibodies (mAbs): in monoclonal antibody therapy laboratory-produced molecules are engineered to bind to certain cells or proteins to stimulate the patient’s immune system to attack those harmful cells.

But the scaling of these potentially life-saving treatments is not easy Because biologics are manufactured through live cell cultures and isolated from natural sources, the production process is demanding and complex, driving biomanufacturers to find ways to make their production processes more efficient and productive.

Last week a new innovation hit that market that is designed to make this manufacturing process even more efficient. Created in the research and development labs at GE Healthcare, MabSelect PrismA is a new Protein A chromatography resin that will help biopharmaceutical manufacturers improve their monoclonal antibody purification capacity by up to 40%.

MabSelect PrismA will help biopharmaceutical manufacturers improve their monoclonal antibody purification capacity by up to 40%.MabSelect PrismA will help biopharmaceutical manufacturers improve their monoclonal antibody purification capacity by up to 40%

Chromatographic separation using Protein A is the most common first step to purifying mAbs, where the goal is to remove the majority of contaminants from the harvested cell culture fluid and to concentrate the product. Protein A is popular due to its high purity and yield, reaching 99% purity in one step. Nearly all mAb processes use Protein A resins as the first purification step[2], and currently there are hundreds of mAbs in clinical development[3].

The purification process: How it works

In monoclonal antibody production, a genetically modified cell produces antibodies that are then separated and purified from the cells. One of the key elements to protein purification is using chromatography resin to which Protein A has been immobilized. Protein A is a naturally occurring protein which has an extremely selective affinity for antibodies.

“The most important part of that process is the first step in the purification, where Protein A selectively picks up the antibodies from that mixture, and in one step you end up with a highly pure product,” says Jonathan Royce, business leader for the chromatography resin portfolio of GE Healthcare Life Sciences. “You also get a high yield, so you don’t lose a lot of your product. That specificity has allowed our customers to rapidly bring multiple antibody therapies to market and produce them in a cost-effective way.”

“Protein A selectively picks up the antibodies from that mixture, and in one step you end up with a highly pure product.”

Royce compares it to brewing beer. “After you finish fermentation, you want to get rid of the yeast so you don’t get a glass full of yeast when you pour your beer. You want a glass of nice, crystal clear beer. It’s essentially the same technology in our industry. You grow and harvest the protein, then you purify it. Protein A is the first step in that purification. It’s the workhorse.”

Since the first mAb was commercially approved in the 1980s, mAbs have grown to represent more than 50% of the biopharmaceutical sales. They are the largest and fastest growing segment of biopharmaceuticals, projected to reach $125 billion in 2020[4].

The biomanufacturing process, and especially the ability to increase the efficiency of cells to produce protein, has improved radically during the past few years, yet purification technologies have lagged behind. This has slowed down manufacturing and led to larger consumption of chromatography resins.

During the past decade, there’s been a steady push to increase the binding capacity of Protein A resins – how much antibody or antibody fragments bind per liter of resin used – to make the purification of mAbs more efficient. Higher binding capacity is important, because it gives higher productivity and shorter manufacturing lead times for biopharma companies.

MabSelect PrismA is the third-generation in the MabSelect family, and it was developed to meet the changing needs of biopharma customers to handle more concentrated antibodies that require more protein to be purified.

It is highly efficient due to its excellent binding capacity, which is critical to determining the resin’s purification capability, including how much resin is needed to purify a certain amount of protein. It’s also significantly more alkaline-stable[5], meaning that it can be cleaned with higher concentration of sodium hydroxide (or lye) to better control cross-contamination risks and bioburden, the number of environmental bacteria living on surfaces and equipment.

“By engineering the protein in a specific way and then also engineering the bead that we attach the protein to, we’ve been able to significantly increase the binding capacity. This together with the improved alkaline-stability was the biggest accomplishment for the research and development (R&D) team,” says Kajsa Stridsberg-Fridén, senior project manager in the research development team of GE Healthcare Life Sciences.

“Protein purification is no longer a bottleneck, but driving higher productivity and shorter manufacturing lead times.”

“That’s a huge increase for our customers in terms of breaking that bottleneck that they have in terms of how much mass they can process,” says Royce. “It’s kind of like turbo charging your car. If you have this fixed asset that you own and you suddenly significantly increase the size of the batch that you can operate, the speed at which you can operate your facility, all of these things start to pay off.”

Manufactured at the Uppsala Center of Expertise in Protein Science

MabSelect PrismA was developed at the GE Healthcare Life Sciences site in Uppsala, where the resin is also manufactured. According to Stridsberg-Fridén this was critical when the product was created, as the teams in R&D and manufacturing were able to make most out of each other’s competence, and they could work parallel.

“We’ve learned so much about Protein A and the ways that we can modify it, that our knowledge will open the door to creating more products in the future.”

The manufacturing in Uppsala is one of the largest manufacturing facilities for chromatography resins in the world, and the resins manufactured there are used in more than 200 FDA-approved biopharmaceuticals[6].

The Uppsala site has currently two factories that provide redundancy in the supply chain for biopharma manufacturers and patients. For patients, this means reliable access to the life-saving medications they need.

Between 2017 and 2022 GE is annually investing up to USD 70 million in the production facility in Uppsala to significantly increase its capacity.

“When you start to use one of these therapies, you want to know that you’re always going to be able to get it,” Royce says. As antibodies become more diverse and complex, Royce expects chromatography to follow suit. Royce expects MabSelect PrismA to be the first step in a new direction for biopharma manufacturing beyond monoclonal antibodies.

“We’ve learned so much about Protein A and the ways that we can modify it, that our knowledge will open the door to creating more products in the future that can address that diversifying pipeline of antibodies,” he says. “That learning is going to enable us in the future to have much more tailored solutions to the diversifying pipeline of therapies that are coming.”

 

 

[1] Compared to GE Healthcare Life Sciences’ MabSelect SuRe LX.
[2] Downstream processing of monoclonal antibodies—Application of Platform Approaches (2017)
[3] Evaluate Pharma, 2016
[4] Ecker DM1, Jones SD, Levine HL (2015): The therapeutic monoclonal antibody market
[5] Compared to GE Healthcare Life Sciences’ MabSelect SuRe LX.
[6] Based on GE Healthcare’s internal market information.