After completing his PhD on increasing monoclonal antibody titers, Farlan Veraitch realized that manufacturing biologics was not the right path for him. The next great frontier, Veraitch envisioned, lay in the differentiation and culture of human pluripotent stem cells (hPSCs).

He focused on automating that process during his postdoc at the University College London (UCL), creating a room-sized robot composed of automated liquid handling equipment, an automated centrifuge, and an automated incubator that went unused and ended up sitting around collecting dust.

Veraitch then launched his academic career at UCL in the Department of Biochemical Engineering, where he worked with Peter Dunnill, PhD, during the biochemical engineering pioneer’s final years.

“He was steadfastly committed, sending me faxes,” said Veraitch. “I would come every morning and have a pile of faxes from Peter about doing exactly what had just happened with monoclonals—the media, vectors, bioreactors, single-use, and development of new processing equipment—coming together. You could now have monoclonals that were cheap enough to go and be distributed widely around the world. All of the conversations with Peter were, “How are we going to achieve this with cell therapy? We need to sort out the media and instrumentation, and how will we track everything?”

Inspired by talks from this new thing called induced pluripotent stem cells (iPSCs) and a talk from Bruce Levin, PhD, University of Pennsylvania professor and Kymriah co-inventor, Veriatch went home and drew out a GMP manufacturing facility for CAR T’s. His manufacturing concept would be the size of three soccer fields and it wouldn’t even be able to manufacture more than 1,000 doses per year.

Next, Veriatch asked Levine if he could return to Philadelphia with him to see the CAR T manufacturing process, which ended up requiring more manpower, space, and reagents than he anticipated—and that was without developing a platform that would provide bespoke solutions to account for patient variability or the differentiation of different cell types at scale.

No matter how many times he tried to draw up a solution, he couldn’t get it to work, especially when considering issues such as flexibility for multiple cell therapies that may have unique maintenance and engineering properties and challenges, as well as the cost of goods. That is, until he broke the problem down from one large contraption to individual, plug-and-play modules.

“How can I replace a cell culture laboratory with a series of boxes that can interact with each other via robotics and barcode scaling to drive stem cell differentiation into photoreceptors or make a new kind of CAR T or whatever in a box that can then be multiplexed and served by robotics as you scale?” Veraitch said.

Veraitch literally went back to his drawing board and began designing interconnected modules. That led him to create Ori Biotechnologies, which was seeded with $9.4 million in January 2020 and pulled in a $30 million series A ten months later, followed by a $100 million series B in January 2022.

Last month, on November 15, 2023, Ori announced new additions to the executive team to support its platform’s commercial launch and enrollment status in their oversubscribed Lightspeed Early Access Program (LEAP). Since 2022, Ori’s LEAP program has been giving leading industry partners, like Inceptor Bio, CTMC (a joint venture between Resilience and MD Anderson), Adthera Bio, and an undisclosed big pharma partner, access to Ori’s proprietary cell and gene therapy manufacturing platform before commercial launch in 2024. These LEAP partners have been doing feasibility testing of Ori’s digitally native manufacturing platform to accelerate their progress toward the scalable production of novel cell therapies.

“We’re on the brink of a revolution in medicine,” said Veraitch. “The whole medical field is waking up to the fact that they should be thinking about any cell modified in any way. That’s where we’re going.”

Laws of attraction

According to CEO Jason C. Foster, MBA, Ori Biotech has three major pillars—biological characterization, automation engineering, and data collection, analysis, and implementation—that support their solution to making GMP-grade cell therapies at scale with flexibility.

“It’s important to give researchers and drug developers the flexibility to tinker when they’re in the lab; we need that flexibility to develop products,” said Foster. “But then, on the other end of the spectrum, we need scalability. We need the ability to do it repeatedly, reliably, and cheaply with high throughput, high quality, and low cost. So, Ori endeavors to bring those two ends of the spectrum together on the same platform.”

To do this, the platform has to be able to know what’s happening inside the cell culture in real time to be able to then modify and adapt the process, which is critical for the consistency and reproducibility needed for GMP manufacturing. As Foster puts it, the cells will react just a bit differently every time something variable is added to the media, and the system has to react to that to prevent having variable cell products.

For all this endeavor’s complexity, two of the most tricky challenges are culturing primary cells and liquid handling. Veraitch says primary cell cultures are far more temperamental than meets the eye, necessitating tremendous microenvironment control from when they leave the donor to when they’re transplanted into a patient. So, Ori created a novel bioreactor system.

“Sometimes primary cells will like to be slightly in suspension,” said Veraitch. “You might want to give them just enough agitation, no agitation, or agitate them a little bit and then stop.”

For fluid handling, moving fluids from one vessel to the next bag or flask and removing fluids requires a lot of manual labor, so Ori developed an automated fluid handling system without tubing, pumps, and bags.

“We put a tremendous amount of effort into moving away from tube building and building sterile connection technology, which is fully automated,” said Veraitch. “I haven’t innovated on the fundamental mechanism of making a sterile connection. What’s the best sterile connector you’ve ever seen? It’s the sterile paper pull tab. It’s amazing. What a brilliant idea! We have used exactly that mechanism and built the automation. The robot pulls the paper pull tab, makes the connections, the media goes in, your sample comes out, and then it disconnects it. And there’s a resealable septum.”

Veraitch said that so much of what’s being done in biotech came from the world of hooking up IV bags in hospitals, saying that cells were never meant to sit in those bags for so long. At Ori, they’re looking at all of these little things—Veraitch said that they even delayed the release of their first module for six months because they thought they could find better plastic.

“People are using plastics that would be used for Chinese hamster ovary (CHO) cell work and applying them to primary T cells,” said Veraitch. “I don’t want to go into much more depth on that, but there’s a big warning for the field. And a lot of that stuff doesn’t even come from CHO. It wasn’t designed for CHO! It was medical device stuff for hospital infusions, and cells were never meant to sit in those bags for so long.”

Honey, I shrunk the GMP cell therapy facility

But much of Ori’s offerings are still very much under wraps. Still, Veraitch reveals a bit about the first version of Ori’s technology, which will hit the market next year: a single-use consumable for cell culture that’s flexible in its functionality and can operate at different volumes, from milliliters up to a liter.

“You’ll see with our first offering that we’ve completely simplified how the manufacturing process interacts with the rest of the world,” said Veraitch. “It is really nice because a human can put stuff in and take stuff out. There’s no skill needed, which is also exactly what a robot needs—a very simple way of interacting with the manufacturing process.”

Foster said that their first module was done primarily for suspension cultures, with the understanding that cell therapies based on T cells are taking up the lion’s share of the cell therapy field.

“The core focus is initially autologous T-cell therapies, and then we can potentially move into adherence cell culture [like] iPS cells. We haven’t seen much progress yet in iPS cells, for example, but we know autologous T cells work. So, we started there and tried to focus on today’s problem, and then we’ll tackle the [allogeneic] problem maybe in five to seven years before we figure that out.”

Overall, the work at Ori should intensify the footprint of cell therapy manufacturing, dramatically shrinking the amount of space needed to deliver a certain number of doses.

“Part of the challenge we face today is those manual processes, and because there’s a lot of people running around them, they’re relatively dispersed,” said Foster. “You might be able to do one product in one clean room, and then you need another clean room to do another product. [Kite Pharma’s] facility in the Netherlands is [204,514] square feet, with a maximum throughput of 4,000 doses a year. If we do our job well and dramatically shrink the footprint, we could do as many as 4,000 doses in 4,000 square feet.”

Foster said they’re modules that stack on top of one another. So, instead of building new rooms and taking up more space to increase capacity, the modules can be added as needed. This also prevents the construction of spaces that go unused.

Bringing personalized medicine worldwide

With last week’s Casgevy approval for sickle cell disease, we can safely say that the era of CRISPR-based cell and gene therapies is here. Indeed, we’ve seen many incredible ideas in developing potential cures.

However, having a cure is not the same as being able to provide one consistently at scale, and that problem becomes much harder when dealing with cell and gene therapies. Foster does not doubt that there will be cell and gene therapies with unprecedented efficacy. But, even with all of these potential developments at Ori Biotech, Foster still thinks they are a long way away from solving how to make bespoke medicines for millions of people.

“How do we mass produce personalized medicine at scale?” asked Foster. “We haven’t quite propped our arms around mass personalized medicine as an industry yet. People are getting cured of cancer at a late stage and have been through all the other options. They’re sick. Then, these patients are cured. It’s a great thing to be able to say we can cure cancer. Unfortunately, we can’t do it for nearly enough people. We’re treating less than 2% of the patients who could benefit from these therapies. All of us have been touched by cancer in some way and know that that’s just an unacceptable outcome—that the other 98% unfortunately have the worst endpoint.”

There’s also the problem of the transportation and shipping of cell therapy products. Using fresh products is better than frozen products that would’ve flown halfway across the world. To bite off a morsel of that hunk of a problem, Forster said that soon, Ori Biotech will participate in a multi-site trial later this year where they’ll manufacture that same product in Houston as well as in another location and then demonstrate that they can produce the same product on the other side.

“It’s fully digital—you could watch both processes happening in real-time,” said Foster. “Put the same ingredients in; hopefully, you get similar outputs. You never know, but at least we’ll know if it’s different and, potentially, why. You can say, well, the temperature was slightly different here, the pH was slightly different there, or we added this an hour later, a day later, or whatever. But that gives us the first hint that you can do multi-site manufacturing in a controlled, monitored way. And that could open up a lot of doors for us.”

Finally, there’s speed. Foster said that if Ori can shorten their manufacturing time as well, then very sick patients would have to wait a much shorter time before they get their therapy back. While these benefits are obvious, said Foster, it’s another dimension that necessitates a whole other set of tools.

That doesn’t mean it isn’t possible.

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