Leveraging the Power of the Immune System to Fight Disease

Marianne De Backer: The other is a platform that we brought in last year, PRO-XTEN™, which is basically allowing us to mask not just T-cell engagers, but also cytokines and other proteins, such that we can really deliver very powerful therapeutics in a very safe way to where exactly it needs to go in the human body. So maybe I'll stop there.

Karen Jagoda: Well, that was a great introduction and a great overview, and I want to circle back to get a little more information about T-cell engagers and what it means to mask the T-cell engagers. That seems to me a science that's becoming more relevant, and it's really part of the secret sauce that you have there, isn't it?

Marianne De Backer: Correct. And it's really state-of-the-art. So maybe just for your listeners, the immune system obviously is the body's sort of first line of defense. It's continuously, there's a whole subset of cells that are continuously patrolling the human body and protecting us from a variety of potential threats. It could be viruses, it could be cancer cells developing. And both viruses and cancer cells have actually have found very smart ways to hide from the immune system and prevent it from doing its job, so to speak. And that allows, for example, in the case of cancer, for cells to grow uncontrollably and eventually develop into a tumor. And that tumor can, of course, then lead to metastasis and very serious disease. So, what we do with T-cell engagers is a type of immunotherapy. We activate basically the body's own immune cells to fight cancer. So the T-cells in the human body, we activate them to really attack cancer cells.

Marianne De Backer: And T-cell engagers have actually been shown to have tremendous potential. There are already 10 T-cell engagers that are marketed and are available to patients, most of them for hematological cancers, but there's also a handful for solid metastatic tumors. However, what has been holding T-cell engagers back is the fact that it can be very, very toxic. So what tends to happen is that T-cell engagers become active outside of the tumor, outside of the tumor microenvironment.

Marianne De Backer: And when those T-cells get activated elsewhere in the body, they can potentially cause severe harm. They can cause a severe form of inflammatory response called cytokine release syndrome. And again, that has sort of been holding the field back. And now coming to your point about what's it about masking that is going to be important here is, so our approach is to take those very powerful T-cell engagers that we know are working, that we know are biologically validated to work and be able to destroy cancer cells.

Marianne De Backer: So, we take those powerful molecules and we basically mask them such that nothing is going to happen when these molecules enter your bloodstream, and only when they reach the tumor, only when they reach a tumor microenvironment, are they going to be activated. So, how does that work? So our technology is called PRO-XTEN™, and we think about it a little bit like a Trojan horse, just like the Greeks use this wooden horse to hide soldiers who then surprised the City of Troy, our PRO-XTEN™ mask, hides or masks the T-cell engagers until, as I mentioned, it really reaches the place where it needs to exert its effect the tumor microenvironment. And when that masked T-cell engager reaches the tumor, then really that fighting power of the TCE is unleashed by actually using protease cleavable linkers. So the mask is being cleaved off, it falls off.

Marianne De Backer: And much like the many soldiers who emerged when treating their target, then the T-cell engager gets activated. It can bind the T-cells on one side of the T-cell engager. It can bind the tumor cells on the other side of the T-cell engager and sort of the cytotoxic killing effect of the T-cells can be unleashed on the cancer cells. So it's really a form of precision that you can deploy to fight cancer cells. And the whole idea is that you can come up with very efficacious drugs, but that are much safer and of course much better for patients.

Karen Jagoda: Wow, that's a great story. And it's always interesting to hear how scientists outsmart the cancer cells. So this masking idea is extremely clever and a very interesting approach. And you mentioned earlier about your AI engine, your dAIsY™ engine. So, how did that help in the development of the masked T-cell engagers?

Marianne De Backer: Yes. Beyond the three T-cell engagers that we have in the clinic, we are working on seven new masked T-cell engagers in drug discovery. And the way that AI helps us is to really test thousands of ideas before we even get to the lab. So it really helps us to speed up the drug discovery process, and it also can really help in improving outcomes, and going to be able to get to basically better therapeutics. So the way it works, it's like running a million of experiments overnight to find a subset of molecules that have the highest likelihood of success. So, without AI in the past, this would likely have taken months if not years to get to it, and it was also very resource-consuming. What it allows us to do now is bring a lot of speed to the process, and we end up with a subset of molecules that have a high likelihood of addressing a number of parameters that we want to optimize in a T-cell engager. And it's a bit of a continuous improvement loop. So we get sequences that we think are going to be good candidates, we test them in the lab, and we feed back the results into the AI engine. And so it's this continuous learning to get to really the best possible therapeutic with all the sort of parameters and elements that we would like to see in the drug.

Karen Jagoda: And have you been surprised at some of the results after you've gone through one or two iterations? Has the AI engine come up with some unique perspective that you might not have considered?

Marianne De Backer: Yes. We have used our AI engine dAIsY™ a lot on optimizing our antibody therapeutics, which is sort of the core of what Vir Biotechnology was initially focused on. And even though we have some of the best world-class, state-of-the-art technology and protein engineers, what the AI engine comes up with is surprising and would not be something that we or our drug discovery team would be able to come up with. So it gives us totally new starting points based on large protein models, et cetera. And again, it's really surprising and it allows us to move faster. There's this faster loop between what we call dry work and wet work, doing the in-silico screening, testing it in the lab, going back to in-silico screening, going back to the lab, so that all goes much faster. And again, as I said, it really leads to unexpected results that give us new starting points for drug molecules.

Karen Jagoda: That's great insight, and it also saves money. It saves money and time by not having to develop something that you thought might be a good solution, but turns out not to be. So, are you finding that you have a higher success rate? Would you say?

Marianne De Backer: Absolutely. I mean, it's for sure increases speed as you say, and it increases success rate. So I think what AI brings to drug discovery, again, it's not theoretical, it's real. We are using it on a daily basis. It's part of our standard operating procedure in drug discovery. So it really has tremendous benefit.

Karen Jagoda: And does your dAIsY™ AI engine work with your PRO-XTEN™ technology?

Marianne De Backer: Yes. The way we are using the dAIsY™ engine is really focused around optimizing the T-cell engagers. And once we have tested and identified the best candidate T-cell engagers, we can then use our PRO-XTEN™ masking technology to put on those molecules. Because one of the great things about our PRO-XTEN™ platform is that it is a plug-and-play. So we can use the same mask, it's an XTEN mask with protease cleavable linkers, and we can use that same mask across all of our T-cell engager molecules. Our three clinical-stage molecules have the PRO-XTEN™ mask, and as I mentioned, we are working on seven in drug discovery. And so we don't, every time that we have come up with a really great new T-cell engager, we do not need to also reinvent the mask. We can really use, again, our plug-and-play platform to put the mask on top of it and then start testing the molecules further.

Karen Jagoda: And does that expand the universe of the kinds of cancers you'll be able to treat?

Marianne De Backer: Yes, so as I mentioned, one of the devastating things is that if you can activate a patient's own immune system to fight a cancer, it's incredibly powerful. And there are these modalities, and they work perfectly. And we know that certain tumor-associated antigens are, again, biologically validated, great targets to go after certain types of cancers, but it's really often the toxicity of the treatment that is holding the progress back. And so the ability now to mask these T-cell engagers, and again, it's not just limited to T-cell engagers, we could also mask cytokines and other proteins, but in this case, the ability to mask the T-cell engagers will just allow you to potentially be able to bring really efficacious and much safer therapeutics to a lot of different cancer types going forward. And again, our focus is on solid tumors and metastatic solid tumors where there's a high unmet medical need.

Marianne De Backer: Our initial clinical trials for HER-2 and PSMA have focused on patients, as I mentioned, who have exhausted all prior lines of therapy. They have really been treated with everything or every single type of approach that is available. And despite all of that, their tumors have continued to progress. So we come in these highly pretreated patients who had really no hope left. And we have seen, very early, but very promising results in patients that obviously have very little hope left.

Karen Jagoda: Before we run out of time today, just tell us about how your background informs your ability to see the future as clearly as you do, and to bring the passion that you bring to this challenge, because this is really something that's been a challenge for so long and you've really made some serious breakthroughs. So, how did you get here?

Marianne De Backer: Yes. I mean, often, as you know in science, when you see progress, people tend to forget how many years and often decades of work have preceded it to get to a certain point. We saw it very well displayed during the COVID pandemic when people suddenly thought suddenly mRNA vaccines were there. But of course, that had been the result of decades of work basically working on that science and optimizing it so that, almost coincidentally, it was ready at exactly that right time when it was needed.

Marianne De Backer: And similarly, in the field of cancer immunotherapy, we have made incredible strides, starting with the checkpoint inhibitors. The masking technology for the T-cell engagers, for example, now seems to be exactly at that point where we can reap the benefit of a lot of work that has been done. I feel a great sense of optimism, especially for patients who, again, are really waiting for solutions. And if we can deliver on efficacy and have safety profiles that are much better with much lower levels of cytokine release syndrome, etc. I think that brings tremendous hope to patients, potentially.

Karen Jagoda: Thanks to my guest today, Marianne De Backer, CEO of Vir Biotechnology, vir.bio. I'm Karen Jagoda, Host of the Empowered Patient Podcast. Thanks for listening, and we will see you next time.