Episode 78: The Power of Nanotherapeutics

Episode 78: Nanotherapeutics

Karie Dozer [00:00:03] I'm Karie Dozer and this is TGen Talks. The T in TGen stands for Translational, the practice of using lab based genomic research to develop better, more personalized treatments for each and every patient. A true bench to bedside approach. Enter nanotherapeutics, a new class of biologics that proves that sometimes the smallest solution is the most effective one, far smaller than a traditional monoclonal antibody. These tiny nanobodies can go where larger molecules cannot and can be combined and designed to attack specific multiple targets while having a less toxic effect on the patient. Listen, as the director of TGen’s new Center for Accelerated Nanotherapeutics explains. And this episode is a deep dive into nanotherapeutics. Our guest on this episode of the podcast is Dr. John Fryer. Thanks for taking time to talk today.

John Fryer, Ph.D. [00:01:02] It's great to be here. Thanks.

Karie Dozer [00:01:04] Tell me a little bit about what you do here at TGen.

John Fryer, Ph.D. [00:01:07] So what we do, what we hope to do is what we're starting out is a new center for accelerated nanotherapeutics. And this is a set of what we hope will be therapeutics that targets anything in the body or anywhere in the body. If we've got a good target to go after, we can develop one of these nano therapeutics to hit that target. And sometimes you want to inhibit it, sometimes you want to activate it. But that's the overall goal, is to get these to the stage where we can make a dent in diseases.

Karie Dozer [00:01:42] Nano therapeutics. Let's back up. Tell me what that is.

John Fryer, Ph.D. [00:01:46] Right. So, therapeutics can fall in a usually a couple of classes. One is small molecule. These are drugs that people are probably familiar with, like aspirin or Prozac or those things. And then there's biologics, which are usually protein based. And the most common form of biologics is a monoclonal antibody. And you probably have heard of these. Humira, for example, is a blockbuster monoclonal antibody. Targets TNF Alpha. It's for rheumatoid arthritis and other conditions. So, the Nano therapeutics is a class of biologics that has emerged relatively recently in the timeline of drug development. And these are formed from Nanobodies, which is the nano part of nano therapeutics. And they were coined this way because they are about ten times smaller than a big antibody molecule like a monoclonal antibody. So, someone coined the term nano therapeutics. I guess they skipped micro and that was sort of the basis of the platform that we've developed and why we decided to call it nano therapeutics.

Karie Dozer [00:03:01] How small are we talking?

John Fryer, Ph.D. [00:03:03] Well, if you can picture in your mind a cell. If a cell is the size of, let's say, a basketball, a monoclonal antibody is maybe the size of a little tiny bump on the outer rim of the basketball.

Karie Dozer [00:03:19] One of the reverse dimples, or.

John Fryer, Ph.D. [00:03:20] We are probably even a little bit smaller than that. But a nanobody is about ten times smaller than that. So, imagine you took a little Sharpie, and you drew the tiniest dot you could imagine on the dimple of a basketball. That's how they would be at that scale. So, they have some advantages that monoclonal antibodies over monoclonal antibodies, they can get in tighter spaces. They can penetrate tissues that are hard to get into. Like the one of the areas that I'm interested in is the brain. And those are notoriously difficult to get things into. So, they have a little more flexibility and adaptability that monoclonal wells are difficult.

Karie Dozer [00:04:02] How long has this been a field of study? I guess I should say, who decided this was something worth pursuing?

John Fryer, Ph.D. [00:04:09] Yeah. Like many things in science and medicine, it just started with someone's curiosity about looking at the immune system of the camel at family, llamas, alpacas, for example. Some quirk of biology allowed them to evolve so that their normal immune system, they make regular antibodies like we make, but they also make this special class where it's just this tiny form that's not to change that zip together to form an antibody molecule. It's a single chain. So, if you picture two Slinkys, for example, that you have to like get intertwined, the ends of those two Slinkys are what forms the binding part of a monoclonal antibody, but a nanobody is a single slinky. And so that single slinky just folds back on itself and forms the ability to bind to a target. And that quirk of being a single chain is sort of the magic of nanobodies. We don't know why they evolve that way. Sharks actually evolved to make these single chain antibodies. Also.

Karie Dozer [00:05:18] Any other animals.

John Fryer, Ph.D. [00:05:20] Lampreys also make a single chain antibody in the.

Karie Dozer [00:05:25] I’m not even sure what that is …

John Fryer, Ph.D. [00:05:26] Lampreys are the sort of the big suckers and they're in the ocean and that's.

Karie Dozer [00:05:30] Why I don't know what it.

John Fryer, Ph.D. [00:05:31] Is sort of eel like, but with a big sucker mouth, there might be a few other species. I mean, you know, one of the things that came up recently, my lab brought to me a paper, and somebody coined the term pico bodies, and I said, What are you talking about? And it turns out cows also evolved. A entirely different form of antibody that is technically called a knob domain because it's a big immune molecule and there's a knob and a little binding stretch of protein that sticks out of it, then that's called the knob. And someone realized that if you just take that knob part, you don't need the rest of the big molecule. Just the knob part is enough to act like an antibody. And so, someone clever coined it peak bodies because nanobodies was taken. We call these colloquially nanobodies and peak bodies, though those terms are technically trademarked, they're still used in everybody that publishes papers on these and grants uses those terms. But the picobodies are probably five times smaller than the nanobodies. And that field, there's only about a couple dozen papers total in the literature about picobodies. So, we've immunized some cows and we're developing picobodies along with the Nanobodies. But it's very early days to know what problems might arise in trying to even use them. But we're going to we're going to make attempts at it.

Karie Dozer [00:06:59] What kind of a small miracle of communication needs to happen for that information to travel from the world of researchers who look at llamas and cows to the world of researchers who are trying to fix things like Alzheimer's disease. Where is this conversation happening?

John Fryer, Ph.D. [00:07:16] Most of these conversations happen digitally now. So, people publish articles and they're immediately available for the most part through PubMed or other indexing services. Someone will be curious and click and say, hey, look at this paper. They come about it at conferences and people will present their work. And this is why going in-person, I mean, hybrid meetings are still very prominent, but there's nothing like face time and just having conversations that that spur new discoveries or new ways of saying, well, you took this discovery. I want to apply it in this way. Nowadays, honestly, a lot of these things pop up on X. Or Bluesky or other really hot forums. I tell my lab all the time, if you don't have an X or a Bluesky and or a blue-sky account, you need to get one. Because now most of my scientific content comes through scrolling through that at the end of the day, when I'm lying in bed and I'm like, look at this paper. So, this has become a medium for dissemination of scientific articles and knowledge in sort of real time.

Karie Dozer [00:08:29] Let's talk about specifically what you're going to research here at Titan.

John Fryer, Ph.D. [00:08:32] What we initially started with nanobodies and picobodies was a disease that was sort of near and dear to my heart, and that's Alzheimer's disease and related dementias. And that's the work that I had started before I came to teach in. And that's sort of the plate that has most filled out so far. And we're going to continue that work. We have a several targets that are known targets, and we have new targets that we're going after. There's another disease that I'm very interested in in sepsis. And this this is a disease where people get sort of rampant inflammatory response and overexaggerated inflammatory response to an infection. It's often deadly. And if it if it doesn't result in death, it results in often end stage organ dysfunction. Brain is heavily impacted. There's a new cognitive function. So, we're going to go after many of those known inflammatory molecules that get kicked up in this. It's probably in people's minds right now for like long Covid syndrome. So, you get Covid, you get this huge inflammation that occurs, this immune overreaction. And there's some overlapping elements with that. So those are two of the big ones. I think what we're going to do now at TGen is really try to explore the cancer space. There's a third class of biologics that has emerged sorry, three classes of therapies. One is small molecule, one is biologics, like monoclonal antibodies or nanobodies or picobodies. The third is cellular therapies. And you may have heard of Car T where you take T cells out of an individual, you engineer them to now target a bad player like a bad cell or a bad protein that goes awry in cancer. And in order to do that, in order to engineer those CAR T cells, you need to have a target that goes after it. And those have to be single chain antibodies like a nanobody.

Karie Dozer [00:10:34] Enter the llamas.

John Fryer, Ph.D. [00:10:35] Correct. Or the cows. Let's not forget about the cows and their picobodies. But either way, you need a single chain antibody that targets that new that new player. And that's what we hope to do here at TGen and in collaboration with City of Hope. And they're their cancer treatment discoveries. It's a relatively new area for us. We've been expanded. My lab has expanded into brain tumors, but other cancers are new to me. And I only have to use your term from earlier a Reader's Digest level knowledge of other cancers. So, I'm looking to my colleagues here at TGen and City of Hope to tell me what should we go after? Help. Help us help you develop these cellular or nanobody therapies. What are the best targets that we can go after?

Karie Dozer [00:11:31] As new as this field is and as these methods might be, is it difficult to find enough researchers like yourself interested in with enough experience in in this field to jump into the research? Or are most of you learning as you go?

John Fryer, Ph.D. [00:11:50] I would say that's a little bit of both. Certainly not just myself, my lab, my team, we have our own cumulative knowledge, and we are using knowledge that others have developed and we're marrying 2 or 3 different strategies. And I think a lot of people that I talk to that aren't in science, they don't realize the creativity involved that's required to think of. I never thought of putting this thing with this thing. And now we have a new dish. And so that takes just some thinking. And I think that's what we do all the time. It's what I do every night is sort of spend a few minutes or an hour at the end of the day just daydreaming and thinking of what could be possible. And some of this there's a there'll be a new discovery that's published and we're like, that's really cool. Can we use that in some way? Can we co-opt that and use it in a way that benefits what we're trying to do?

Karie Dozer [00:12:58] Does that method work in reverse? What I mean to ask is if you come up with a therapeutic that maybe doesn't work the way you intended, but you see that it might work for someone else whose research is very closely related to what you do, How do you share that and see its possibilities for something that would be a positive?

John Fryer, Ph.D. [00:13:20] That's a great point and I think that happens all the time. So, there may be some things that we would orphan in our lab and we would say, Well, we made this, this great thing and it didn't work for what we wanted, but maybe it works beautifully for something else. And I think that's part of the scientific body of knowledge is we're big proponents of publishing our work. If you work purely in an industry setting for a biotech or pharma, they're not motivated to disseminate their failures. And if it's a registered clinical trial, they have to. But other things, they do things all the time and they realize this just doesn't.

Karie Dozer [00:14:00] Work and they junk.

John Fryer, Ph.D. [00:14:01] It and they don't they junk it, and they don't want to tell their competition. They want their competitors to waste their time. But that's the beauty of being in academia, is that we disseminate that knowledge. Like, look, we did this whole thing, and we developed this new potential treatment. We tried it out in a model system, and it failed. And we're big proponents of publishing that failure so that others know, we were going to do that too. There's no point. Those failures, negative results, we call them in science, are critical to keeping things moving forward and not wasting time.

Karie Dozer [00:14:32] I think negative results is a great way to classify failures. I think we should do that in all fields. Yes. What's it like to have the City of Hope with its incredible patient base? I mean, they're treating people every day. And now that TGen and City of Hope are joined, it seems to give you a much bigger pool of available, willing patients, people who are wanting to know what's the next best thing we could try.

John Fryer, Ph.D. [00:14:57] Yeah, I think that was a really key part for me is having access to clinical knowledge and knowing that if we develop something that there's an immediate outlet that we could design a clinical trial with people who know what they're doing, that's not me and try to see whether what we're developing could work in having a huge organization like City of Hope. It was super attractive to me. I don't know that if this was whatever the timeframe was eight years ago or so before teaching became part of City of Hope, I don't know that teaching would have been as attractive for me. There's other ways to find clinical partners and make it work, but this is sort of in the family and it makes it so much easier to envision keeping the pipeline moving.

Karie Dozer [00:15:51] When it's all said and done, what would you like to. What would you like to have found? Discovered? Say that you brought to market even in terms of therapeutics, in what you're researching, what's the big prize?

John Fryer, Ph.D. [00:16:05] That's a very open-ended question. I hope that we are able to at least make a huge dent in a serious disease. I don't know yet whether that will be Alzheimer's or one of the related dementia is Lewy body dementia, frontotemporal dementia, ALS, etc. I don't know whether it will be sepsis. I don't know whether it'll be cancer. I'm not naive and I realize that it may be none of those. We're going to press on the gas pedal as hard as we can and make that happen. If we can make a dent in one of those. And I'm using the word dent because I don't want to say cure. Sure. I think a lot of these diseases as we move into, or new age of medicine are more about maintenance. And if we can, for example, on Alzheimer patients, they starting to show a few signs. If we can just keep them there and not let them progress. I think anybody would take that win. And I think many diseases are going to end up being that way, especially these age-related diseases and conditions. So, if we can do that, if we can, if we can cure it, great. But if we can at least keep them where they are, that's a huge win.

Karie Dozer [00:17:22] Is there a particular reason that neurodegenerative diseases, ALS and the like are your passion?

John Fryer, Ph.D. [00:17:29] It happened sort of organically. I didn't intend to go into this field. I joined a lab at WashU in Saint Louis, and it was an Alzheimer lab. And I always found it interesting. And once you get immersed in something, I say this about a lot of things. We have a very different pot of projects going on in lab. Anytime you delve into anything scientific, if you're curious, it's interesting how plants develop, how bacteria grow. All those things. Everything. If you take a real look at it is interesting. So, this is just the one that captured my early interest. It's the one that has remained unresolved. And until recently, maybe with some caveats, treated. So, it's the one that is closest to me for that reason.

Karie Dozer [00:18:19] What have I missed? What do you want someone listening to know about either your research specifically or how you do it?

John Fryer, Ph.D. [00:18:27] I don't know that you missed anything. I would say that we. We have a platform that we're exploiting for a handful of things to start. What I would hope if someone's listening, and they've got ideas. Please reach out to me. I talk to friends and family constantly, and it always amazes me where someone thinks they're asking a totally naive question and says, what if you tried this? And I had never really thought of it. And that's one of the reasons why in science it's good to have youth. I have several graduate students and lab people getting their Ph.D. or M.D., Ph.D. And those individuals are critical because they come at questions with some naivety. That is great. And they don't know that that may just be a total failure, but they're unafraid to ask the question. And if you ask the question, you're like, okay, that seems crazy, but is it crazy enough to work? And that sort of philosophy in science, I think, is most of the really successful labs incorporate that. Not being afraid to ask those questions.

Karie Dozer [00:19:39] So how does someone find you if they have a crazy idea? I don't know how found you want to be, but. Right. Be careful what you wish for.

John Fryer, Ph.D. [00:19:47] Right. So, you can look me up on the t gen websites. I think my contact information is there now. I've only been at TJ in about a month now, but I think the web page and the contact information is on there and I answer emails constantly. Sometimes I get behind and but I try to always respond to people who have reached out to me over the years that are just people in the community.

Karie Dozer [00:20:13] Well, I hope you don't get too many crazy ideas that you need to hire an assistant to respond, but I do hope you get some some cool ones. Thanks so much for taking the time to talk to them.

John Fryer, Ph.D. [00:20:23] Thanks.

Karie Dozer [00:20:24] For more on TGen’s research, go to TGen dot org slash news. The Translational Genomics Research Institute, part of City of Hope, is an Arizona based nonprofit medical research institution dedicated to conducting groundbreaking research with life changing results. You can find more of these podcasts at TGen dot org slash TGen Talks, Apple and Spotify and most podcast platforms. For TGen Talks, I’m Karie Dozer.