Conditionally Active Cancer Therapeutics - Talking Biotech Podcast #489

Hi everybody, and welcome to this week's Talking Biotech podcast. Now we're in the 11th year now. And one of the unpleasant realities of time is that the people you care about might experience declines in health. And I've had friends, I've had colleagues, spouses of colleagues and friends that have experienced hardship in their lives with degenerative disease and long-term developmental disease, things like cancers, different cancers are really start to plague your core. And one of the things you notice is that Although we've come a long way in terms of treatment, that some of the treatments, especially for advanced care, tend to be extremely harsh and that the treatments can be as hard as the problem itself, to the point where people who you really care about and love are saying, I want to defer treatment and just let it go because the treatment is so harsh. And, you know, we're wrestling with this with a few folks right now, I know, and my heart goes out to them. during these trying times. But what if there were drugs that could be tuned and drugs that could be targeted? And we're seeing this more and more with immunotherapy approaches. But what if there were some drugs that were specifically targeting tumors or other tissues that could then deliver a therapeutic environment directly to those tissues? and alleviate the problems that happen in other types of cells or other types of tissues. And this is one of the issues that we're seeing with conditionally active therapeutics. How do we come up with drugs that can be processed or targeted in a way that makes them specific for a given problem? And this is really exciting. So I'm speaking today to 2 representatives of Bonum Therapeutics. This is Dr. Neela Patel.

Hi.

She's the Chief Business Officer. And Dr. Diane Hollenbaugh, she is the Chief Scientific Officer at Bonem. So welcome to the podcast.

Good to be here with you, Kevin.

Yeah, I'm really excited because this is such a cool topic. And, you know, we're going to discuss the conditionally active biologics. This is an emerging class of drugs. It's apparently safer, more effective than conventional therapies, and specific in its application. But let's start with the current situation. And I maybe framed it a little bit, but you're much more the experts than I am. What are the problems that conditionally active biologics are trying to solve?

So the real problem is that when you have a drug, you take a pill, you get an injection, that drug goes everywhere, everywhere within the body. And it doesn't— there's no way that it knows where to go. You sprain your ankle, you take an ibuprofen, it doesn't know to go to your ankle versus your wrist or wherever else. And so you get that activity everywhere. And so if it is an activity that can cause other problems, like a toxicity, like with chemo, it goes everywhere, not just to the cancer, then, then you have that problem of that toxicity. And it's both horrible for the patient, but it's also that you can't necessarily get as much drug there as you need. And so the problem is how to get the drug. to where you need it to be, only active where you need it to be, and not be active anywhere else.

Yeah, that's a really interesting angle because I love your example of ibuprofen for a sprained ankle. I mean, it's a perfect example. But what are some examples of current therapies with significant side effects from toxicity that conditionally active biologicals show potential in addressing?

So there's a number of different ways people are trying to do things that are Conditional or targeted. So just to start with a little bit, people talk about the ADCs, antibody drug conjugates, and really what it is, is finding different ways to specifically bring the drug right where you need it to be. For the conditionally active biologicals, what we're doing is we're using biological drugs, not small molecule drugs, but proteins. And here what they are is these are proteins that are— we're taking from nature. They're things that— Your body already uses in different ways, and we're trying to use them as drugs. Now we're taking 'em outta their normal context, so they go everywhere, they do all kinds of things. So one specific example is IL-2. So IL-2 is an approved drug. It's amazing. It, what it does is it targets the immune system and it can drive an immune response against your cancer. And so for the subset of patients for whom it works, they basically, we cautiously use the word cure, 'cause they get these long-term responses in a very small subset, an indication. The problem is not Not only does it lead to that, the flip side is that the patients often end up in the ICU or worse. There's patient deaths because of the drug itself. So that's a pretty big, pretty big flip side to that efficacy. And the problem is, is that protein, it does all these other things that are toxicities that aren't related to the good thing that it does. And so trying to find a way to take that biological protein and target it Right to the cells that need it, that lead to efficacy without having to do it doing all this other business that's the toxicities.

Yeah. I think I've seen this described as on-target, off-tumor toxicity, right? You're, you're, you're hitting the target, but there's other problems associated. Is that what I'm looking at? It is.

It is. And there's also one more specificity to that, that when people use that phrase, so like IL-2, a way to say that is that there's IL-2 receptors in lots of places. And so the IL-2 goes to all those places that don't have anything to do with the tumor. And so that's what it is. It's on target. It's an on-target activity. It's what that protein is meant to do, but it's not on the tumor and it's not related to that tumor biology that we need to be affecting.

Yeah. And I, I guess this is as we enter the world of, um, immunotherapies and some of the ways that these, you know, just have been astounding. We've been talking about 'em for a few years here, and there's a lot of interesting things we're learning about them as we go along. And why has it been so difficult to reduce the toxicity of immunocytokines and make them more effective?

So the immunocytokines, part of the issue is that they are so powerful. That's, that's the other side of that pancake. They're so powerful. And so being able to have them be targeted and not active anywhere else is difficult because you inject them, it doesn't take very much to get all this other activity. Mm-hmm. So it doesn't take much at all. And so even if it's targeted and, you know, it's hooked to an antibody that takes it to the right cells it needs, it's still active and it still brings all that toxicity with it. Really get— being able to get around that systemic activity is where we have to go. And that's where the conditionally active ones come in.

Yeah, that, that's kind of where we're going. So getting around the systemic issue, if you have a conditionally active biological, How are they different from what we have already? I guess that's really the big question, you know, just for the listeners to bring everybody up to speed. How are they different from what we're doing now?

In the place where you need it to be, but also it's off everywhere else. That's a very important other side of that. And so people have been trying to do this in a number of different ways, different kinds of masking techniques. I think one of the ones that people are probably most familiar with might be the proteases. So in cancer, tumors make— it's just the nature of tumors is they have these proteases around them. And so people take these masks, make them so that they block that activity until they get to the tumor. Then the proteases cleave off that mask and now you have activity there. So things like that that people have been trying to do to get rid of that systemic activity. So it's only active where you want it to be. Yeah.

And I think so just for the listeners that proteases are these proteins that do protein processing according to sometimes a very specific cleavage. And we see it like in insulin is a great example that you have pre-pro-insulin that 2 proteolytic cleavages give us the active form of the hormone. The same thing is applying here in the delivery of the drug that a locally produced Protease might be able to do that and unmask it. The other way of approaching this might be through something like monoclonal antibodies. And these are useful tools introduced in treating specific disorders already. We saw it in COVID, other places. But can you tell me a little bit about what monoclonal antibodies are and why are they useful tools in treating specific orders— disorders?

So monoclonal antibodies are part of our normal immune system. It's what our body does to fight infections. It makes these proteins that are beautifully specific, and they're, we always draw them as a Y because they are a symmetric molecule. And so we draw them always as a Y 'cause they have 2 binding sites that are identical. And what happens is when your body, you know, your immune system sees an invader, you get the flu, you have a virus, you have antibodies that bind to that. And as soon as your B cells know that they're making one that's a good one, they make a whole lot more. And the key is that what we're using them for to take— what we've done to exploit them is that they are fabulously specific. And so we can create them in the lab to make these very specific antibodies. Now, biologically, what antibodies do is they block things. So your body will make antibodies against the flu virus, and it'll make antibodies that block that flu virus from infecting your cells.

Right.

Which is beautiful, right? So we can do the same thing. We can make these antibodies to block what we want it to block, whatever we want it to do, what we want it to bind to. And over the last several decades, we've learned how to create them, how to manipulate them, how to produce 'em at scale so they can be a drug, cuz that's also a really important part of it. You gotta be able to make it. And so they have this fabulous specificity of whatever it is we design them or make them or create them to bind to so we can use them as drugs. Yeah.

So this is really cool. So we talked about this idea of, you know, proteolytic cleavage in order to activate something, others with, you know, directed targeting, you know, like, but what is the mechanism behind how a conditionally active biological is turned on and off? Because this is a big deal. I mean, you're making a monoclonal antibody. So is it really a, you've said before, an unmasking of function, or is it really targeting the drug to the right place?

Both? It's a bit of both. Yes. It's a bit of both. So we use the antibodies. So first, so really what we need is we need 2 things. We need to be able to get the drug to stay in the right place, and then we need a way to turn it on and off. So the first step, get it to the right place, that's a regular antibody. That's how antibodies work. And a regular immunocytokine can bring that cytokine to the right place. It's not off, but that antibody can bring it to the right place. The mechanisms that we can use for turning it on and off, there's a couple of different ones. So one is the proteases that I mentioned, so now you have the cytokine and it goes to its place. It hangs around now in the tumor 'cause it's stuck there by this antibody and it has time to cleave and then it releases the cytokine. For what we do at Bonem is a little bit different. We use antibodies slightly differently. We have a mechanism where we use the antibodies as the off switch as well as the turning on switch. So it's slightly, it's a little bit different use of the antibodies. So in our system, in our technology, we're using the antibodies both to deliver it to where it needs to go, as well as to be the on and off switch for the biologic that we're delivering.

Okay. So this is kind of cool because we talked about antibodies again, you know, I mentioned COVID, for instance, and how this might be able to turn off the virus by binding to specific sites on targeted cells, for instance. So there's ways of like that kind of interfering with, you know, binding, that kind of thing. But when we're talking about your example, Let me backpedal a little bit, 'cause we talked about immunocytokines. You brought this up too, is tell me what that is exactly and why they're important in cancer therapies.

Immunocytokines are a class of drugs that, uh, we're still working on how to get them to be good, useful drugs. They're emerging. But what an immunocytokine is, is it's an antibody that has a cytokine attached to it. So that antibody is what brings it to a target. It brings that along, that cytokine, to that location. So a regular immunocytokine is just that. It's a cytokine that's attached to a targeting antibody to bring it somewhere in particular.

I see. So what, what exactly is a cytokine for those of us who aren't doing, you know, cancer biology?

Apologies. I slipped into be— between those words a lot of times. Thank you for Calling me out on that. So cytokines are a particular class of proteins. We can make conditionally active biologics, biologics being the broad one. A subset of the biologicals are proteins that are these cytokines, and cytokines are proteins that are active in the immune system. And they're part of the system where different immune cells talk to each other. So a given cell might get activated in a certain way, and it wants to— they need to induce a response in another set of cells. It may produce these cytokines and it secretes these proteins that now signals on these other cells to amplify a response or direct a response or turn off a response depending on what it is.

Oh, that's an excellent example. So excellent description. So are there ways in which cancer cells or other types of neoplasias actually evade cytokine signals?

They do. They get selected for. So part of what happens when you have cancer is that you, you get, you, we get cancerous cells in our bodies all the time in our Mm-hmm. System clears it out. It's part of a normal process. It's part of that process of something turning into cancer that those transformed cells that are the cancer cells have a way to get around this immune response, whether that's hiding from it and cloaking or finding ways to silence the immune system around them. So yes, the cancer cells themselves, the other thing the cancer cells do though, in addition to potentially producing the things that suppress the immune system, they also recruit other cells. They form this network, they bring in these other cells that also do that sort of thing. So a solid tumor is more than just a ball of transformed cells. It's this network of all these other cells that the transformed cells bring in as well. And so these cytokines and the biologics that we're talking about act, can act both either directly on the transformed cells.

Right.

Or on the immune cells or the stromal cells, the other cells in that environment that that cancer cell needs. And if we can mess that up for that cancer cell, then it'll die. And we now, we have a therapy.

Yeah. And that's especially important because cancer cells are, inside solid tumors, are constantly evolving. And so these things are changing all the time. So having some sort of therapeutic, which has a little more of a general aptitude to be able to address a large number of cell types as they're changing, still would be a really potent thing.

So what?

What is the biggest challenge in this new class of drugs? So for instance, you know, challenges come with different types of therapies because of their molecular complexity. And how do these affect analytical development?

So some of the ways that we do this, it does affect the analytical development, and we always have to make sure that we're doing something, you know, it's one thing to make interesting proteins, it's something more to make a good drug. And so it has to be something that can be produced, can be stable, can be analyzed, that actually has the right properties once it's injected into an animal, including a human, all of those other pieces to it. I think all of the things that we're doing for the conditional biologics, they follow all the same kinds of rules of the things that we've learned for other kinds of biologic therapeutics. We've been, you know, it's been decades now that we've been working on different kinds of biologicals, and we've learned so much, both how to test it ahead of time to predict if it's going to be good or not, how to design it, all of those sorts of things. So we bring all of that to bear. Now, that said, these can be potentially complex molecules. They're not simple, potentially, but I think that we know how to do that in the design phase. And so that is our responsibility in the early phases to make sure that it's something that we can make and produce and use.

No, very good. But these are conditionally active. Are they conditionally inactive? Can you shut them off once they're on?

Yes, depending on the mechanisms that's used for that conditionality. So the protease-cleaved ones, you can't, right? Once that protease cleaves that, now you have an active cytokine where, wherever it is, you know, it's now active and it can become systemic. With what we're doing at Bonum, um, our mechanisms, our mechanism is reversible. It's fully reversible. So when it's bound to the target that turns it on, it's on. If it comes off, it turns back off. And that is a really nice feature of the technology we've been working on.

No, very good. Now, this is really exciting because of reasons I stated earlier in the introduction, you know, new classes of therapies, being able to tailor the immunotherapy response. This is a big deal. And so we're talking to Dr. Diane Hollenbaugh and Dr. Neela Patel, both of Bonem Therapeutics. And this is the Talking Biotech podcast, and we'll be back in just a moment. And now we're back on the Talking Biotech podcast. We're speaking with Dr. Diane Hollenbaugh and Dr. Neela Patel all about conditionally active therapeutics or conditionally active biologics and ways in which immunotherapies are being tailored to treat specific cell types. One of the things that maybe came out from the first part of the talk was we really didn't dive too much into the immunobiologics and the immuno, you know, this class of drugs. And so maybe, Diane, could you gimme A little bit more on that. I mean, what exactly are we talking about when we refer to this class of therapeutics?

So when we talk about immuno-oncology, what we're talking about is finding ways to have the immune system recognize the cancer and get rid of it. So there, the cancer cells, as they evolve, they have to have these mechanisms of hiding from the immune system or turning off the immune system. And what we're trying to do is to reverse that. And as you said, cancer cells, they change all the time, so it's difficult if you have something that's just targets one specific thing, then they change. But your immune system is very good at adapting and seeing lots of different things in something it's trying to get rid of. That's what it does. And so if we can trigger this immune response, get the immune response to get rid of it, not only will you get rid of that solid tumor that you're seeing, but you also get rid of those cancer cells wherever they might be. So you get rid of all those other things as well, which is just really nice. And then if they start to grow again, your immune system's right there to take it back out, 'cause once it's seen it and knows how to do it. It'll keep doing that. That's, that's what it does. And so the immuno-oncology area is really trying to find ways that where we're training or re-enlivening or getting rid of the mask that the cancer cells are using so that your immune system gets rid of the cancer. And we are not targeting the cancer cell itself. We're driving the immune system, letting the immune system do that business.

Yeah. And so, so just to clarify, you know, maybe if we think about, uh, chemotherapy as ways in which we're targeting cell division or checkpoints in cell cycle to limit the way cells divide. This is actually training the systems that are within the body already to recognize aberrant cell division and aberrant cell types that normally would be hidden because of the nature of cancer cells. Is that where we're going?

Absolutely. That's perfect. That is a great way to describe that.

Well, that's really cool. So, When we think about this from a business standpoint, and, you know, in the landscape of all the approaches that are being taken on, how many companies are currently in this space, and what kind of problems are they targeting?

You know, there's, of the ones that we can see, and we of course know that in biotech there's often companies working in stealth mode, but there's about a dozen or so companies in the area of conditionally active biologics. And, uh, you and Diane have had some nice conversations around companies that use protease-activated technologies. You also referred to ones that would be, um, immunocytokines, so just targeted, but not on or off, just, it's only the getting it to the right address. And of course, for those circumstances, you now have a fully active, theoretically, cytokine That can be toxic everywhere. So the companies that are in that space have found that they need to reduce the activity of the cytokine itself, because otherwise, even though it's being dragged to the right place, it's being administered to your whole body and you're still getting the toxicity. So that's, um, you know, another bucket. And then there are ones where people are using pH or, um, metabolites as a way to control the activity, either of the antibody or of a cytokine. So in round numbers, about a dozen. Um, it's a, it's an emerging field. There's definitely people, you know, in the clinic now. Um, so far there hasn't been an approved drug yet, but that's not because things are going poorly. It's an, it has to do with how young the field is. And we expect, I mean, even at time that we've been a company, we've seen new entrants into the field. So we expect that this is going to be an expanding area.

I certainly agree. I think that there would be more and more because it's making the area of immunotherapies only more directed and specific and less toxic. So broadly speaking, if we go across the entire healthcare landscape, what's the market opportunity here?

The market opportunity will depend on the particular cytokine that you're using and where we already know it can be active. And then we can also look and see where we believe it will be. In all of these cases, the markets are very significant, meaning that, for example, our lead program today, which uses interferon alpha, We believe that near, well, we know every single cell type in the body has interferon alpha receptors. So the receptor is present and we are targeting it in a way that is, to a target that is present in the majority of cancer types and at a high prevalence. So it's not like a lot of patients who are unlikely to respond will be dosed with our drug. So we think there There's a lot of unmet need, and we do believe that the cytokines that we're using and that others are using, 'cause others see the same opportunity that we do, will really be beneficial for patients.

Well, you know, I think—

How about—

Oh, I'm sorry, go ahead.

Just to add a little to it too, from a broader class of conditional biologics, I mean, we're talking about immuno-oncology and the focus of what we're working on, but from the broader concept of something that's conditional, That really can apply to many different state— targets many different therapy areas and needs beyond oncology even. And so we do think that there's, if you, you know, the human condition, there's lots of things where having something that's targeted could be beneficial. And that's one thing that we've really been interested in is making sure that whatever we're doing also might enable people who might, we might wanna go into different therapeutic areas, different disease states and things like that in a broader way, not just immuno-oncology even. Right.

Yeah. Could you gimme a good example of that? Like maybe, um, you know, autoimmune disease? It seems like an obvious one, or? Yeah.

I mean, if, if we could, if we knew for a given autoimmune disease what things the immune system was responding to, and we could turn off just that, as opposed to the more, like now what we need to use is a lot of broad immunosuppression, and some of it's somewhat targeted or directed at least a little bit in how the biology is. But if we knew for sure that, This is what we need to turn off, and we could send that to it. Maybe just a really simple way to say, if I knew how to get something as an anti-inflammatory just into the joints that were inflamed, wouldn't that be lovely? That would be fabulous.

And it seems like those kinds of targets are potentially there because biologically speaking, these cells should have specific targeting domains, right? And so this is pretty exciting stuff. So let's go back to maybe kind of the business side of that.

Sorry.

No, believe me, I like the science side, but the business side we sometimes have to touch on a little bit is it's an exciting time for the field and more people are in the space, more companies in the space, and making generalizations is really difficult. But when you talk about your company, when you talk about Bonum, how is the approach differentiated from other companies working in the same kind of space?

I think the main ways in which we're differentiated is something you raised right up front, is that we are targeted and we have both an on and off switch. And it's actually the same switch, which is quite convenient for us because, as I mentioned, like, there's a number of companies working in the targeted space, but they don't control, they don't have an on-off switch. And then there's other companies who are working in the on-off switch space, but they're not necessarily targeting. And then there's ones like protease activated where, yes, it's off in the periphery when it's still intact, but after cleavage, that activated molecule can go anywhere. So, you know, in theory, you're reducing the amount of systemic exposure, but you're not really having a true off switch. So— We do believe that, um, our technology is differentiated and will offer patients, um, broader therapeutic index. So a bigger window between where you get efficacy and where you see toxicity.

And just by perusing the website and looking at other information, there really is an interesting origin story here. So could you tell me a little bit about how Bonem was founded and the roles of the Good Therapeutics team?

Absolutely. So, it's a great question. We started as a company called Good Therapeutics, working with the same technology platform and developing it. And our lead program, PD-1-regulated IL-2, was of interest to several pharmas. And ultimately, we sold that program to Roche, and we did it as an And what might be of interest is that Roche probably wouldn't have paid anything more for the whole company, and our platform would not necessarily have been deployed widely. So we made the decision, and Roche was actually quite happy to just get the product that they wanted. And then we spun out the platform technology. All the employees became employees of Bonum the day after they were laid off from McGood. And the next morning they came in, they were Bonum employees. It was all very And what it meant was that we could continue to use our platform and make new drugs for patients. So it worked out, I think, well for all parties.

Are they still in your Rolodex?

Absolutely. Absolutely. Conversation's always ongoing.

Well, let's talk about that. I mean, what are some of the other exciting parts of the R&D pipeline and their current status in that pipeline? You know, what is the LEAD program, and why did you select that one to kind of lead this development of this type of strategy?

So we have— our LEAD program is, as Neela mentioned, is a stroma-targeted interferon alpha. It brings interferon into the tumors, and we know interferon is this very powerful cytokine, and it does All the things that you want it, would want within that tumor with respect to the immune system, the stromal cells, the cancer cells. And so, but, but again, we can't use it systemically. So it's perfectly suited for our technology where we're taking it right, right into the tumor. It's off everywhere else, on in one place, completely off everywhere else. So that, that program really was— One of the things that we do is we always try to look for places where the biology is well enough known so that we know what to do, so that we know what the need is and what it could be. And how to test for that. And that one is perfect for that because we know that the interferon is exactly what you need in that setting. And we had just the right target to be able to target it.

So you're talking about interferon. Give me a little bit of a hint about what interferon is and why it's so important. Like, you know, of, of all the cytokines, what's going on with interferon? We heard about it in the late '70s as the cure for cancer. So give me more information about this and And, you know, why it has deleterious effects on non-target cells.

So it is, because it, like, all the cells express the receptors for this, it can act everywhere. And that's partly because one of its functions is to tell a cell that it shouldn't be keeping on going. So it acts on all these different cells, but it acts in different ways. Within the immune system, what it is in the immune system, it's really a link between your innate immune system. So this is the part of your immune system that That first reacts when there's, you know, you have a bacteria, it doesn't know what it is. It says, oh no, there's a bacteria, and it tries to recruit everybody else and tell all the other adaptive cells. And so that piece of that function, what it's doing is that it's stimulating all those cells that are support your adaptive immune resis— response. And when we talked before about immuno-oncology and what it is, that adaptive immune response is what we need. So what interferon does, Is it can signal to the cells that are part of the adaptive immune response, the cells that'll actually kill the tumor cells, but it also signals to all the cells that are a set of cells that are suppressive to those cells. And it tells 'em, stop being so suppressive. Don't do that anymore. Differentiate into something good. And then it also signals to the dendritic cells where this is a set of cells that are necessary for showing the immune system what it needs to respond to. And what interferon does there is it says, there's something going on, grab all this stuff and show it to the immune system in a way that makes it respond. And so that's what those cells do in response to interferon. So that's why within the tumor, all of those things are what we want to have happen. And interferon alpha is uniquely the cytokine that can do all of those different things.

I think we're really at a wonderful point. In terms of the field at large, and I mean scientific understanding of how the immune system works, the mediators, the signalers, and so on, to be able to identify really key cytokines or other biology that can make a difference. Like, there's enough precedent in the clinic to say, go this way because— patients do respond, but the toxicity is not appropriate or not tolera— it really does not work out for them. And we're able to really build on that in a way that I think has the potential to be transformative.

Oh, very good. All of this makes so much more sense now. Okay. So we've covered a lot of this already, but when we're talking about interferon alpha and how that's being used, how does the dual-binding antibody platform play a role in this and how it allows interferon interferon alpha to deliver the right agent to the right target, creating a very powerful therapeutic in the right place.

So the way our platform works with dual-binding antibodies is this. So antibodies, they can bind to a protein and block its function. So we can make an antibody against interferon that now keeps interferon from being active. And so if I have that, that's not going to be active anywhere else because it's it's stuck on this antibody that keeps it from binding to its receptor. What we do is we make a dual-binding antibody, meaning that that antibody can also bind to something else. And so in our example with this, our lead program is LRRK15. So it can bind to interferon and be a blocking antibody, or it can bind to LRRK15, but it can't bind to them both at the same time. So then what we do is we take that interferon and we create a tether Just a linker, and we link it to that antibody. So now it's linked on that antibody, that is its blocking antibody. So it's off, goes all around the body anywhere you want it to go. It stays off because it's stuck to its blocking antibody. But if it gets to where its target is, now that antibody is bound to that target, that interferon is free to do its business. So now the protein— the drug is—

Is free.

Bound to the cells we want it to be active on, tethered with this very active interferon right there. The reversible piece, if it comes off, it just binds again because it's just a blocking antibody.

Yeah. And then this is what is, is such a pivotal part of this particular technology as an immunotherapy that can be delivered to the right place. And just by— it's, it's, is this like a, this is a physical change in the molecule, right? When one binds the other. is loose to interact. Is that what's happening?

It's, it's really just a competitive binding. So when the antibody is bound to one, it's covering up the site for binding to the other. So once it binds to LRRK15, it's not able to bind because it's now bound to LRRK15. It gets in the way. It's just a competitive, straight up a competitive binding.

So it has more affinity for the receptor on the cell than it does for It's a ligand for the interferon alpha. So when you bind the receptor, now that interferon's free to interact.

Yes, with its receptor thing.

Oh, well, throughout this entire discussion, we've talked about dual-binding antibodies, but antibodies by definition, at least in my naive understanding, is that they have one good binding site. So what's happening here?

So absolutely, as an antibody person, we always think of that an antibody binds, one antibody binds one thing, and that unique specificity is one-to-one. But the fact is that the binding site of an antibody is big enough that there's plenty of room for us to create binding sites for more than one thing. So in our antibodies, what we do is we just take advantage of that fact that there's enough real estate there to have 2 distinct binding sites for 2 distinct things that overlap like this.

Now, this is all good stuff. And the thing for me is I get so excited when I hear about exciting new ideas and new technologies, especially in the area of immunotherapy that can solve these problems. But how do you envision development of this particular product type, drug type, with a timeline and ultimately be able to proceed to the market?

So that's where, in drug discovery and development, it's the development of an individual agent is all about what it does and that the properties of that specific thing, not by what technology it came from. So in that sense, what we have is we have a drug that we have a very clear understanding of the in vitro properties, as in how much does it take for it to turn on? How much does it take to turn off? And we'll do all the same things you would do with any other therapeutic, which is to do all this modeling between in vitro and in vivo data, toxicity data, concentrations, all of those things to get an understanding of where do we start in the clinic? And then what also do we look for in the clinic? What other biomarkers might there be to be able to follow? And in that sense, this is no different than any other therapeutic where we start from what does it do? How do we assay for it? What do we expect it to do? What happens in the patient? How do we learn from that for where to go next?

We don't really anticipate timelines that are different, as Diane is saying, than for anything else. And because we think really carefully from the very moment we start on a program about being able to manufacture it at scale and have it be stable and so on, we don't anticipate that there will be any particularly slower pieces in preclinical development. So we think our time to market should be similar, honestly.

Well, what about possibilities to accelerate that? It seems like a lot of companies are crawling over each other to be the newest and best technologies and take advantage of collaboration, for instance, with companies that are developing the best new ideas. And so what is the current environment like for financing and collaboration?

Financing for privately held companies, challenging. Collaborations, very much appreciated and an active area, both on the pharma side and on the biotech side. And ultimately, we as Bonum do not imagine that we will run pivotal trials, in other words, Phase 3s, where it's— you're enrolling large number of patients, and it's very costly, and there's a kind of infrastructure you need for that. So we not only are interested in collaborating, as Diane alluded to earlier, to make new molecules, for example, in autoimmunity or to treat fibrotic conditions or metabolic conditions, we are also always looking at partnerships for pharma who would then take our molecule and get it through the last part of development and commercialize and sell it. So you're quite right that we're going to, we know we're gonna need those partners. We talk to them. all the way along so that they, you know, when we're ready with a dataset, they're like, oh, I remember this was a project we're really interested in. We really like the science. It makes sense. Now you've got something that really is at a milestone. We're interested in talking about a transaction.

And that's all good, you know, and I would assume that that would be the case, that there's folks who have the infrastructure to accelerate your work. But can you comment on the idea of having a biotech company with a cool idea that looks like it's working, that you have good preclinical data. What's it like doing that in the current environment?

Challenging.

Yeah, I think challenging.

So challenging is the best, maybe, way to say that. And frustrating might be part of it as well sometimes. But I think that one of the things that we learn in drug discovery, just in general, is resilience. There's always headwinds. There's always things, hurdles. And the way I look at it is that this is just another hurdle that you know, our molecules are going to have to get through, um, and we'll find a way. I think that for me, for what we're doing, I believe very strongly in the biology of what we're doing, that we're creating something really valuable and it will find a way. We will find a way for that to come forward, even if it's, it's challenging. That's just how it goes.

I mean, you mentioned biotech, but it's actually not different in pharma. Both Diane and I have multiple experiences where a program dies 8 deaths and on the 9th time is when it gets through. And so, you know, you just, you just have to know that you got to keep pushing forward and being persistent and resilient because this is not different, sadly, than it is anywhere else. It's normal.

And especially when you're, especially when you're moving into a bit of a newer area, there's always that resistance. There's always the, that, you know, well, I haven't seen this before, so it must not be right. Well, you haven't seen it before, but it's, there's It's hard to do that piece. That happens within a big company. It happens in little companies. It's just human nature. It hasn't worked yet. Well, the keyword there is yet. We always have that word, yet. So, there's always that challenge, especially moving into a new area, a new space, or a new technology. The need is still there. And one thing I think that will— that always accelerates a program is as soon as you get a little bit of good data, You get some clinical responses, you get some interest, you know, that'll really accelerate. That'll really— so sometimes in a way, getting started is the harder part. And then once the molecule starts to show what it can do, brings its own momentum.

And this really brings me to the question that my guests usually hate because they don't have a crystal ball, but I always ask the crystal ball question. And that is, what is the most exciting part about the future that you think this class of drugs might bring? And maybe I could start with Diane and then go to Neela.

For me, what it does is it opens up areas of biology that we can't manipulate any other way. So we've known that there are certain cell types, certain biologies, certain things we want to be able to do all the way back to IL-2. We know IL-2 does really good things, but we can't harness it. We don't have the tools to harness it. And now what we're doing, and we're developing these ways to actually harness these these really powerful biologies in these really targeted ways that I think there's just so many opportunities to be able to create therapeutics that'll really make a difference.

Now, Neela, what do you think?

I mean, I agree with Diane. The excitement for me is that we really have the potential for complete responses, durable complete responses, which Which is equivalent to a cure in sort of, you know, ordinary parlance, right? And not just for a few patients, but because these mechanisms are universal, really the applicability is for many, many patients to benefit. And because I'm a scientist by training, I really genuinely believe the benefit for the patient will lead to financial benefit for investors, for, you know, whoever spent the money to get the thing to the market and is selling it. So I feel like if If you lead with the science that way, you'll always come out in the right place on the other side.

And that ties to, sorry, that ties, ties to something that you started with, which is that, you know, you're on this planet long enough, you've been touched by cancer. You, someone you know, a loved one, a family member, friends, you're touched by that. It's out there. And so having things that can treat that, I like to look back at how, you know, 20, 30 years ago there were cancers that were considered, you know, Really bad, a death sentence and things. And there's some now, I had a family member diagnosed with cancer and the question to me was, is it a bad one? It's like, well, now today, not so much. 20 years ago, yes. So that is the thread that we look for. I want someone to be able to say, is it a bad one for all of them? Not so much. We have something. That's, that's the goal. That's what we're after.

Well, this is all very exciting. If people want to know more about Bonum Therapeutics, where do they look online?

bonumtx.com. Come on over. And, uh, we have both information about our programs and also links to our presentations, publications, and more publications to be coming in the future.

Well, very good. Well, Dr. Diane Hallenbaugh and Dr. Neela Patel, Well, thank you so much for joining me and do me a favor and please let me know when the big breakthroughs happen because I'd love to talk about them here. This is just a seed we plant and then later on we'll love to follow up with how this is changing everything. So thank you very much for your time today.

Thank you.

Thank you so much, Kevin.

And to the listeners, thank you very much for listening to this week's Talking Biotech podcast. Get excited about more therapies using novel approaches. And I know if you go back through the archive, we've talked about these for a couple years, different ways in which we're trying to solve the most insidious problems in human health. This is just a different approach that together with many other approaches may lead us to very good therapeutics in the future that can help, help solve some of the biggest problems in the human condition. Thank you for listening to the Talking Biotech podcast, and we'll talk to you again next week.