With the goal of expanding access to antibody-based drugs worldwide, the Bill & Melinda Gates Foundation is turning to industry to innovate its methods of manufacturing the proteins. In the last two months, the organization signed deals with Biogen Inc. and Just Biotherapeutics Inc., fostering programs to reduce costs and increase yields that benefit both the for-profit and not-for-profit enterprises.

 

On Aug. 8, the Gates Foundation and Biogen announced a project to improve antibody production and manufacturing techniques, using eight undisclosed expression systems that include yeast, fungi and algae. The idea is to search for alternatives to Chinese hamster ovary (CHO) cells, which have served as the workhorse of antibody manufacturing for 25 years. Biogen will conduct the research over an 18-month period, and the results will be made publicly available.

 

Financial details were not disclosed but the organizations are contributing roughly equal amounts, according to Stephen Hadley, senior program officer for vaccine development at the Gates Foundation. Hadley said Biogen is also contributing an antibody to use as a benchmark and some of the analytics.

 

The partnership comes two weeks after the Gates Foundation invested $8 million in a series A2 round for Just Biotherapeutics, a start-up focused on streamlining antibody production. A further $6 million was invested by existing investors Merck & Co. Inc., Lilly Asia Ventures and Arch Venture Partners. Last year, the foundation awarded the company $24 million in grants over five years to develop low-cost HIV antibodies and technology platforms for low-cost biologics.

 

Despite the success of CHO cells for supporting antibody production, the yield has hit a ceiling after years of optimization; however higher yields and more streamlined manufacturing are needed to reduce costs for emerging and third world markets.

 

But according to Tim Moore, EVP of technical operations at Kite Pharma Inc., since the 1990s when a platform based on CHO cells was established, there has been little motivation in industry to innovate or switch expression systems. Moore was previously SVP and global head of Pharmaceutical Technical Operations Biologics at Roche’s Genentech Inc. unit.

 

“There were hardly any players in that space, so it made a lot of sense just to build upon [the early methods] and then come up with different ways to get higher titers,” he said.

 

Hadley told BioCentury that was the first challenge he faced when he joined the organization three years ago and was tasked with exploring mAbs for infectious diseases at production costs that could be practical in focus regions such as sub-Saharan Africa and South Asia.

 

“Most of the antibodies and biologics developed for the world marketplace enjoy extremely nice margins, so for cost of goods there has never been a pressure driver on the industry to figure out how to lower costs,” he said.

 

Hadley said there was little interest among most of the biotechs he spoke to about developing better methods. “Frankly, people are pretty set with their processes and installed capacity.”

 

However, the Gates Foundation’s approach was to make “catalytic investments” that will get the field to move in a new direction, said Hadley, and to find industry partners that see a commercial benefit to improving the technology that complements rather than competes with the organization’s interests. “We don’t have any alignments on products; this is all around technology. Their portfolio of products is different than our interests.”

 

Whereas the funding for Just Biotherapeutics supports lower-cost methodology for CHO-based manufacturing, the Biogen project is looking beyond CHO cells, and is using an open model that hopes to engage other companies that might see the upside of creating a next-generation, low-cost platform.

 

Jorg Thommes, SVP of technical development at Biogen, told BioCentury the field has reached an inflection point. “We’re now at this point of saying ‘OK what’s next?’ Will it be mammalian cells forever? Or is there an opportunity to get even better and to get to the next step change in productivity?” he said.

 

WHOLESALE CHANGES

 

According to Thommes, the ongoing adherence to CHO cells has not been for want of trying to find alternatives. The problem has been that there’s been no coherent or coordinated strategy to replace the cells.

 

“People have been trying out alternate expression systems for a long time,” he said. “And they’ve been executed sporadically with different focus. And there has never been a real head to-head comparison of many alternate expression systems with the current high-productivity mammalian cells.”

 

Overall, the efficiency of antibody production from CHO cells has increased by a factor of nearly a thousand in the last 25 years, with common yields approaching 3-6 grams per liter of CHO cells, due largely to a greater understanding of CHO cell biology, said Thommes. “We’ve gotten much, much better at understanding what these cells need to grow and thrive, so we can maximize their number in a reaction system and the time that we can keep them alive and happy.”

 

But those improvements also capped progress. “Mammalian cells make proteins that are very well tolerated by humans and are fully functional. So, there was no need to look outside of that mammalian cell box because we got so much better at it,” Thommes said.

 

However, the main drawback is the long growth cycle, he said. Mammalian cells are typically cultured for 10-14 days during a production run, compared with 2-3 days for yeast or bacteria. Microbes are used at large scale to produce biologics like insulin and human growth hormone, which are made in yeast and bacteria, respectively

 

Thommes said that the main advances have been in the “upstream” part of antibody manufacturing, which involves protein production, where using lower-cost media and achieving higher titers has improved productivity and reduced costs. But the principal need is in the “downstream” part of the process which involves protein purification, where costs have remained stagnant.

 

“Alternate expression systems with increased productivity will most likely present a different, possibly leaner, background to isolate antibodies from. This could open up intriguing opportunities for disruptive downstream processing technologies,” said Thommes. In particular, he thinks replacing traditional chromatography methods with other unit operations might be interesting, and the current focus on virus inactivation and removal steps for mammalian cell expression might be reduced with alternate hosts.

 

Hadley believes that the results of the Biogen project can seed bigger advances once opened up to the research community. “I think the trajectory would be similar to what happened with CHO. Eventually organizations, when they landed on CHO, they brought their own CHO cell lines and vector technologies into their own organizations, optimized them, and controlled the IP around that.”

 

JUST SAYIN’

 

By contrast, the investment in Just Biotherapeutics is meant to help the start-up double down on CHO cells, using protein engineering and infrastructure improvements to reduce costs. “It’s the extreme opposite of the very large-scale stainless-steel model that’s been very successful, but there’s a production cost floor that it’s difficult to figure out how to break through,” said Hadley

 

The company was started by a team of Amgen Inc. veterans, who aim to introduce changes throughout the process, from molecule design to facility layout, to lower costs tenfold and bring cheaper antibodies to developing markets.

 

“You have to look at it holistically. You have to look everything from molecular design for manufacturability all the way through the plant and how well the plant is designed. So, we can optimize in both directions,” said Just CEO Jim Thomas.

 

Hadley said the Gates Foundation is solely interested in infectious disease antibodies in the project, which it wants to expand to third world nations, following the model of Synagis palivizumab, a humanized mAb against respiratory syncytial virus (RSV) from AstraZeneca plc’s MedImmune LLC unit.

 

For the HIV project, the target product profile calls for a subcutaneous product dosed quarterly. The aim is to use protein engineering to enable low-viscosity formulations at about 150 mg/mL, and modifications to the Fc region to extend the half-life.

 

Hadley said the Gates Foundation grant covers HIV antibodies from four different academic groups funded by the Collaboration for AIDS Vaccine Discovery (CAVD). The antibodies include eCD4-Ig from The Scripps Research Institute and 3BNC117 and 10-1074, which are in Phase I trials, from The Rockefeller University.