Davide Zocco: From Petri dish to patients

Davide Zocco, Image Courtesy of Lonza

This episode is sponsored by Lonza. Click here to listen to the full podcast episode

Sally: It’s all very well and good knowing the basic science behind how we can use exosomes to deliver drugs only to the places we want to target, but somebody has to make those exosomes before they can be injected into a patient.

That’s where Dr Davide Zocco comes in. Davide is Head of Exosomes Development at biotechnology company, Lonza and that means he’s responsible for taking everything we’ve learned about exosomes and turning that research into an efficient manufacturing process. I sat down with him to find out more about that process…

Sally: So I'm imagining you've got this flask of all of these cells floating around in solution. Presumably you're keeping it at about 37 degrees. Lots of nutrients. They're all producing these little tiny exosomes. How do you separate out the exosomes from the rest of the ingredients in the flask once they've been made?

Davide: The first step is to remove, through a sort of filter, the cells from the exosomes.

Davide: But that is not enough. You need to further purify the exosomes, removing all the cell debris, all the junk coming from dying cells, DNA and so on and so forth. So you need to apply multiple steps, which include technologies like chromatographies to make sure that you are only purifying the exosomes and not the impurities.

Sally: And all of these steps presumably put a great deal of stress and wear and tear on whatever's in that solution. How stable are these exosomes?

Davide: The exosomes are fairly stable. It is known in the field that they can withstand acidic conditions, also some mechanical stress. We do have analytical tools to measure the integrity of the exosomes during the process and at the end of the process to make sure that in fact, we are not damaging them.

Sally: What are the big challenges to overcome in scaling this up? Because the whole idea is that we've got this cutting edge research now saying that actually exosomes could be this amazing treatment, but someone's got to make the exosomes and we can't be doing it in small little flasks. So what are the big steps that you are focussing on at the moment to try to make it easier to produce these in the quantities that we'd need, cheaply enough that they're useful?

Davide: We are developing technologies to essentially increase the productivity. As it is now it's too low.

Sally: Is that the productivity of the cell? The cell isn't producing enough exosomes or the system?

Davide: Productivity here is a term that includes many different aspects. It pertains to the step in which the cells produce the exosomes. So for instance, we can modify the cell line to produce more exosomes per cell. We could modify the cell line to reduce the number of impurities that are sorted into the exosomes, which is also very beneficial. And that is one aspect where we are working on increasing productivity.

Davide: Then you have the aspect of increasing productivity by improving the purification step, because the purification that we have is not perfect. Only 30% of exosomes that through the process are in the end purified. So how do we increase from that 30% to a higher number of exosomes, but at the same time, pure?

Sally: My background is as an evolutionary biologist, so every time a cell divides, you've got the potential for evolution. And so you've got billions of cells in vats that are going to be dividing. And you've changed their genetics; that's what we want. We want them to have specific genetics to produce exosomes.

Sally: How do you make sure that the cells haven't evolved into something else and are producing a slightly different exosome to the one that you thought they were making when you first put them in? Can you actually look at the level of the exosome to see what's happening? Is there technology for that?

Davide: Yes. And this is where another key piece of the puzzle, the story that we're building, comes in. We are developing dedicated characterisation tools. And we can do that at the single exosome level, in terms of molecules inside of them and the different subpopulations of exosomes, because you can imagine all these little bubbles are different from each other.

Sally: And then once you've got these few mls of pure exosome liquid, how easy is that to store, to actually give to a patient? What does the process look like once you've succeeded in making the exosomes? How does that then become a treatment that a patient can use?

Davide: One beautiful thing about exosomes is they can be frozen.

Sally: Oh, that's handy.

Davide: Yes. They can be frozen. It typically gets frozen at -60 degrees and can be shipped quite easily.

Sally: And then once they're at room temperature, how long do they last for?

Davide: They're pretty stable. We're talking about days of stability of these exosome at room temperature.

Sally: And that's gotta be quite important because, I mean, we've all learned a lot about the cold chain process with the development of COVID vaccines, but you can imagine that they can be kept cold until they get to cities, but then once they have to branch out to individual medical practices, it's quite handy if you've got a few days to do that and not a few hours to keep them alive.

Davide: Absolutely.

Sally: And say you work out a way to produce exosomes for one of the major cancers, for example. How long do you think it will be before we can make enough exosomes to treat everyone?

Davide: So of course it's going to depend on the indication. What we do know is that we need to increase productivity between 10x to 50x to meet demand. And so we are still at the beginning.

Sally: Are we talking a few years? A few decades?

Davide: No, we are targetting within three to five years.

Thanks to Davide Zocco from the biotech company, Lonza.