Pod Insights a16z Podcast Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) About this episode with @carolynbertozzi @lr_bio
This is the second episode in our new show, Bio Eats World, a brand new podcast all about how biology is technology. This show now includes Journal Club, where we discuss groundbreaking research articles, why they matter, what new opportunities they present, and how to take the findings from paper to practice.
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Transcript Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.
0:00 Sonal? Hi, everyone. Welcome to the A6 and Z Podcast. I'm Sonal, editor in chief at Andreessen Horowitz. And what follows is the very first episode of Journal Club, which you actually heard me introduce to this show feed much earlier this year, but it is now part of our separate new show BioEats World, a podcast all about how biology is technology. As a reminder, Journal Club dives deep into a new scientific article with the authors of said article and/or A6 and Z and other experts on the implications of the breakthroughs, as well as how to translate them from paper to practice. If you'd like to continue receiving Journal Club episodes, produced and hosted
0:43 Sonal? by A6 and Z bioeditor Lauren Richardson, please subscribe to BioEats World wherever you get your podcasts. And if you'd like to learn more about the expanding A6 and Z Podcast Network, please visit a6andz.com/podnetwork. Thank you for listening.
1:01 Speaker 01 Hi, I'm Hannah, and welcome to BioEats World. I'm Lauren, and this is the first episode of Journal Club. So tell me, what's Journal Club all about? So Journal Club's on Thursdays, and this is where we take a recent scientific article and discuss it, either with the authors of the paper or with our own internal experts here at A16Z. And we highlight what the paper shows, what new opportunities it presents, and how to take those research findings from paper to practice. Okay, so tell me, what's this first paper all about? The first paper is titled "Lysosome Targeting Chimeras for Degradation of Extracellular Proteins," and it was published in Nature. That's a lot of words. What do they actually mean?
1:42 Speaker 01 The basic idea is that diseases are often caused by proteins that have gone haywire in some way. So there's either too much of them, or they're present in the wrong place or at the wrong time. And the idea here is to create a new kind of drug to degrade those proteins. So if there's too much of the protein, you're reducing the levels. If it's in the wrong place or the wrong time, you're removing it from that area. And that's a really exciting new type of drug molecule. Okay, cool. So what's important about this paper? How is this moving us forward? This paper is really exciting because it's targeting a whole new class of proteins, some of which have never been able to be touched by any other kind of drug. And who is the guest joining you for today?
2:25 Speaker 01 Right. Today, we have the senior author on the paper, Carolyn Bertozzi, who is an amazing scientist. She's a professor at Stanford, and her work focuses on creating new methods to perform controlled chemical reactions within living systems. So we're going to lead off with Carolyn describing how conventional drugs work.
2:48 Speaker 02 So most conventional medicines act by binding to a target, a pathogenic driver. That's a protein in your body that's contributing to a disease. And they act by what's called occupancy-driven pharmacology. They bind to that target and block its function. So ibuprofen binds to an enzyme and blocks its activity, which then blocks an inflammatory pathway.
3:23 Speaker 01 So the normal typical drugs are working by binding proteins and blocking their activities. But in the last 10 years, we've seen some really exciting alternatives to drugs that rely on this specific model, with the most well-known and the most well-developed being what's called a ProTAC or a proteolysis-targeting chimera. So how do these new drugs differ from what we just described, these standard typical drugs?
3:48 Speaker 02 So that concept came out of academic labs in the early 2000s. And the two people who published the defining papers in this area were Craig Cruz from Yale and Ray DeShays, who at the time was at Caltech. Now he leads research at Amgen. And they had this idea that another way to shut down a pathogenic protein would be to target it for degradation. And around that time, there had been some breakthroughs in our understanding of how nature normally degrades proteins. Because she has to be able to do that. New proteins get made, old ones get degraded.
4:29 Speaker 02 And a central mechanism for degradation of proteins inside the cell is that they get marked with ubiquitin chains. And that's a signal for the proteasome, which is like the meat grinder inside of the cell, to chop up these proteins and destroy them. And there are enzymes that put these ubiquitin chains onto proteins that are destined for degradation. And so what Cruz and Duchesne realized is that you could build a molecule that artificially bridges the gap between a target protein and this ubiquitin machinery. And with that molecule, you could basically get a protein ubiquinated intentionally and therefore degraded. So that was their conceptual idea.
5:14 Speaker 01 So in the course of the normal function of the cell, you have proteins being produced, but you also have proteins being degraded. And so one of the main mechanisms for degrading protein is by the ubiquitin proteasome system. And that's where the cell says degrade this protein by adding ubiquitin molecules onto it, and that pulls it to the proteasome where it gets chopped up. But what a protec does is it's a molecule that can bind a target protein, so the one that you want to degrade, and bring the enzyme to it that adds the ubiquitin tag, adds the flag. And then that brings it to the proteasome to be degraded.
5:52 Speaker 02 Right. And the reason that was so transformative is that not all proteins are easy to block, actually, with drugs. There are lots of proteins that are not enzymes, and they don't even have a pocket, really, where you could put a drug and it would block the function. So the cool thing about these protecs is that they don't have to bind in a place that would block its activity, but instead bridges the gap to an enzyme that puts the ubiquitin on and drives the degradation. So the promise really is that the Protac or the Targeted Degradation Approach expands the druggable proteome. Because now more proteins can be drugged because you have this other way of doing
6:37 Speaker 02 it through degradation and not just blocking.
6:39 Speaker 01 So you're using the endogenous mechanism that the cell already has for tagging proteins that you want to be degraded and using it now to target a much wider range of proteins than you could if you were only able to target those that have, you know, a really nice pocket that could be targeted with an activity inhibitor.
7:00 Speaker 02 Right.
7:01 Speaker 01 So what are some of the limitations of these approaches?
7:05 Speaker 02 Well, the targeted degradation field began with the Protacs, but it has expanded over the last 20 years to include other types of protein degraders. But all of these processes function on proteins that are inside the cell, in the cytosol or in the nucleus. And meanwhile, there's this whole other world of proteins which are outside the cell. So these are proteins that are displayed on the cell's surface, the membrane-associated proteins, many of which, the majority of the molecule is outside, presented on the surface where it's not accessible to the proteosome. And as well, there are many proteins that are just completely secreted by the cell
7:50 Speaker 02 and just released into the extracellular space. And those extracellular proteins are about 40% of the human proteome. So that's a pretty big chunk of the pie that is not available to the Protac strategy. And many of these proteins, these extracellular and cell surface proteins, are important targets for drug development. And, you know, my lab had been working on a variety of different cell surface molecules and secreted molecules that contribute to things like cancer immune evasion, for example. And many of the molecules we wanted to drug were really not druggable using the conventional blockers. And that's where the lysosome targeting Chimera, Litac, research started.
8:36 Speaker 01 I see. So the Protacs that you described are a really exciting new modality, but they are limited in that they can only target the proteins that are within the cell. And there's this huge world of proteins that just are not available to be targeted in that way. And they aren't ones that rely on occupancy of like a particular binding site. They can't be targeted by those types of drugs either. So they're really kind of an unmet need for drugs to target them.
9:05 Speaker 02 I would go even further and say sometimes even targets that can be drugged with a blocker, you can get a more potent effect with a degrader at lower doses, right? So even secreted and sol surface molecules that have been successfully drugged with monoclonal antibodies, you might actually do better if you convert over to a degradation strategy.
9:29 Speaker 01 Why do you think that is? Why do you think they're better than activity modulators? Or is that not known?
9:35 Speaker 02 Well, I think with occupancy driven pharmacology, you can't ever get like 100% of the target protein blocked. There's always an equilibrium and you have to constantly pump the system with enough drug to keep the occupancy as saturated as possible. By contrast, the degrader can bind to a target and get rid of it. And then bind to another target, get rid of it and bind to another one, get rid of it. So you're just reducing the level of the target protein. But because there's the potential for one drug molecule to mediate the degradation of multiple targets, you could get a deeper inhibitory effect in principle.
10:16 Speaker 02 And that has now been borne out even in some early stage human clinical studies with Protacs. The same could very well be true with Lytax. Of course, it's a much earlier technology, so we don't know that definitively. But there's, I think, a rationale for thinking that way.
10:32 Speaker 01 Yeah, it's kind of like pharmacodynamics 101 that you have a reversible inhibitor and you're going to have this equilibrium. But with these degrading molecules, you know, they don't get degraded when they tag the protein for degradation. They have a benefit of one degrader molecule can target a huge number of target molecules. So that's really interesting that even in like a head to head comparison on a known druggable target, that you can possibly get a better effect by degrading as opposed to inhibiting. So now that we have the background on Why we need this new type of drug? Why you decided to go after extracellular and membrane-associated proteins? Let's get into the details of how you develop these molecules. And as we mentioned, the Protax co-opt this endogenous pathway, the ubiquitin proteosome
11:16 Speaker 01 pathway, but they can't reach these proteins outside the cell. So what cellular pathway did you co-opt to degrade those proteins?
11:24 Speaker 02 So again, through as nature degrade these extracellular and circulating molecules. And she does this through what's called the endosome lysosome pathway. So cells will basically internalize and engulf molecules from the extracellular space into endosomal vesicles that go through a maturation process to become the lysosome. And the lysosomes, people from their cell biology classes might recall, that's the organelle within the cell that has a lot of degradative enzymes. So lysosomes can degrade proteins, polysaccharides, lipids. There's a lot of hydrolyses within the lysosome.
12:06 Speaker 02 And so we conceived of an idea where we would develop bifunctional molecules where one part binds the protein that you want to degrade and the other part binds a lysosomal trafficking receptor system. So that's the key is that lysosomal trafficking system. And it turns out that in human biology, there are about a dozen known receptors whose job it is to grab stuff either from the membrane or from the extracellular space and pull it into this endosome lysosome pathway for degradation. And so what we have done is hijacked those pathways by basically building molecules
12:47 Speaker 02 that interact with those receptors and then attaching them to a molecule that binds a target of interest. So that's the structure of the lytop. A binder on one side for the target, a binder on the other side for our lysosomal trafficking receptor.
13:01 Speaker 01 Right, so nature has already come up with a way to degrade the proteins that are membrane-associated and extracellular. And you just developed a mechanism that allows you to say which protein you want to degrade and then extracting it from the extracellular space and degrading it inside the cell.
13:19 Speaker 02 Yeah. And one of the best-known lysosomal trafficking receptors is the so-called mannose 6 phosphate receptor. And mannose six phosphate is a sugar epitope that is found on lysosomal enzymes. And that allows them to be trafficked to the lysosome by this receptor, the mannose six phosphate receptor.
13:42 Speaker 01 So you have this sugar molecule that if you attach it to a protein, that's going to take it into the lysosome. So how did you engineer the specificity to target the protein that you wanted to the lysosome?
13:56 Speaker 02 So you need a binding molecule that is very specific and ideally also very high affinity against your target of interest. And, you know, in our early proof of concept studies, we chose targets to degrade for which there already were high affinity, high specificity antibodies available, several of which are already approved human medicines. So for example, we're interested in the epidermal growth factor receptor as a target for degradation. This is an important cancer target, EGFR. It's overexpressed or mutated in many cancer types where it's driving the proliferation of cells. And we made a lytic out of a human drug called cetuximab.
14:42 Speaker 02 It's an antibody against EGFR that is used, you know, in the oncology setting. So that process of taking an antibody against a target and just decorating the antibody with the mannose six phosphate groups, that converts it to a lytic.
14:56 Speaker 01 Great. So antibodies are molecules that our immune system produces and they are incredibly well tuned to bind one specific protein. And there are many drugs that are actually antibodies, but their main function is to just block that protein. And what you did was you took that therapeutically active antibody and added the glycan molecules that you needed to turn it into a lytic. So now not only is it blocking the protein, but it's shuttling it into the lysosome to be degraded. It almost gives it like an extra function, like making it even more effective at disrupting their target's function.
15:35 Speaker 02 That's right. Also, the more we learn about biology, the more we are appreciating its complexity. And I think we also are now understanding that most proteins have functions that are not just binary, you know, like an enzyme is either on or off. Most proteins have multiple dimensions to their function. They interact with other proteins. So when you block a protein through an antibody, or through a small molecule inhibitor, there are probably other interactions of that protein that you're not affecting, which still contribute to the biology. And when you degrade the protein entirely, you take away all those dimensions of its function. And so it's not just that a degrader can
16:19 Speaker 02 be more potent than the inhibitor in an axis of biology. I think the degrader can have more axes of an effect.
16:28 Speaker 01 Do you think that that could lead to possibly off-target effects of disrupting kind of a bigger network than you anticipated?
16:36 Speaker 02 That's a good question. And I guess it depends on where you draw the line between on-target and off-target. Because take a protein like EGFR. The biology of that receptor is driven by its interactions with other components of the signaling pathway. You know, EGFR binds its ligand, the epidermal growth factor. And the consequence of that is that triggers a signaling cascade. And so if you inhibit the activity of EGFR by just blocking, you don't affect any of the downstream signaling biochemistry. However, if you drive the degradation through the lytic approach, and some components of that signaling machinery come down with it, that is actually a direct hit, I would say, that's
17:20 Speaker 02 on-target, right? Because you're hitting not just EGFR, you're hitting the complex that drives its biology, right? So again, the biology is never transacted by a protein in isolation. It's by that protein and the network of its interactors. So I would argue that if you can degrade some of its interactors, it's a more profound influence that's on-target.
17:40 Speaker 01 So now that we've talked about the details of your study, how you develop these bi-functional ligands that can bind to a specific target protein and shuttle it into the lysosome for degradation, let's zoom out and put this research into the broader perspective. What are some of the new opportunities that this work provides?
17:59 Speaker 02 We're now exploring therapeutic applications of the Lytec technology, and we're interested in extracellular targets that have been very, either difficult or really just impossible to drug, and there really is no options right now for patients for certain disease settings. So for example, we're very interested in diseases that involve aggregation of proteins in the extracellular environment. Proteins that in their misfolded or unfolded forms lead to toxic aggregates that could cause tissue damage. And so these are diseases that are often called amyloid diseases. The ones that are most familiar to people would be neurodegenerative
18:43 Speaker 02 conditions like Alzheimer's disease, Parkinson's disease. It's been very difficult to figure out, how do you get rid of these protein aggregates that are pathogenic in the extracellular space? They're not really amenable to inhibition. The process by which they form is often not well understood. You really just want to get rid of them, right? You want to degrade them. And I think the Lytec approach is perfectly situated to take on peripheral amyloid diseases. For example, there's a condition called light-chain amyloidosis. Antibodies have a heavy chain and a light chain. So in patients with this condition, there's too much light chain all by itself, and it's not stable, and it's forming amyloid aggregates,
19:25 Speaker 02 which deposit in organs throughout the body, and they're toxic. The standard of treatment for these patients is very poor. So we think the Lytec approach could be interesting in that setting.
19:36 Speaker 01 That's a perfect example because those light chains don't have an enzymatic function. They don't have a nice pocket that you would be able to stick a drug in. So the ability to pull those out of the extracellular space and degrade them with a lytec, it sounds like a perfect match between disease physiology and drug modality.
19:54 Speaker 02 Yeah, so that's an example of sort of secreted pathogenic molecule or system of molecules. There are other membrane-associated targets that we think the lytec is well suited toward. And one class of molecules that my lab is really interested in are called mucins. These are transmembrane glycoproteins that are huge, and they're kind of the giant redwood trees of the cell surface, so to speak. And they're known to be associated with cancers. And cancers that overexpress these mucin molecules, they tend to be very aggressive and very difficult to treat. And we've done a lot of work to understand, like, what's the function of these mucins that's oncogenic? And the bad news, from the perspective of
20:38 Speaker 02 drug discovery, is that a lot of the biology of these mucins is a physical biology. So they're pathogenic because of their stiffness and their rigidity and their physical effects on the cell surface, not because they interact with a receptor, for example, which maybe you could block, right? And so what do you do when the function of the molecule is a physical one and not a biochemical one? And I think this is where you just want to get rid of them. I think you just want to degrade them. And fibrosis, right? That's a disease setting where there's pathogenic accumulation of collagen scarring. And, you know, that's hard to think about how to drug that, you know, at least at the endpoint
21:22 Speaker 02 of the disease where you have this material that you really just want to degrade. And so again, I think a lytec strategy would be interesting to test in that setting.
21:32 Speaker 01 A lot of really important applications for this. So what are some of the elements of the lytec design that still need to be optimized to turn them into therapeutics?
21:42 Speaker 02 So this was the version 1.0 of the LyTAC technology. And the work that's now going on is basically the second and third generation improvements. And those improvements have taken several forms. So first of all, we are interested in improving the structures. So the second generation LyTACs have a new chemistry so that the conjugations are site-specific, that we can engineer the part of the antibody that actually gets coupled to the mannose six phosphate groups. And with our new chemistries, we can make different geometries of LyTACs and find what is the best geometry for a given target. And it probably will be target-dependent. So we're kind of now writing the rulebooks.
22:27 Speaker 02 And in the publication, the LyTACs we made are built from these known antibodies. We are now developing LyTACs from other kinds of binders, including small molecules that might otherwise have been blockers. We're now converting them to degraders through the LyTAC approach. Another dimension that we're expanding upon is the lysosomal trafficking receptor that we hijack. So the mannose six phosphate receptor was a great starting point. It's expressed in virtually all cell types. But there are other systems that are more specific for different cell types or different tissues. So our next LyTAC family are targeting a receptor called the acylo glycoprotein receptor,
23:11 Speaker 02 which is a liver-specific lysosomal trafficking receptor. And we have a pre-print that we posted on Chem Archive on this new generation of LyTACs.
23:23 Speaker 01 Yeah, liver-specific makes a lot of sense because we were talking about fibrosis. Liver fibrosis is a huge problem, and that's caused by too much collagen in that area that you want to break down. But you don't want to break down collagen everywhere in the body, you know? That's really a critical molecule. You could get wrinkles, God forbid. It's really important in your skin, it's really important in your joints. So to have that specificity of where you want to target the degradation is really important and an additional, like, strength to this approach.
23:53 Speaker 02 Yeah, and I think that then hints to a broader universe of LyTACs that target different receptors that are tissue-specific in different settings. That's the tip of, hopefully, a big iceberg of interesting new degraders.
24:09 Speaker 01 All right, more to come. So we'll end with, what is the key take home message from this article and from our discussion today?
24:16 Speaker 02 I think the most important point is that this exciting, still relatively young field of targeted protein degradation has just been set free from the confines of the cell. So extracellular proteins should now be added to the list of potential targets for a degradation strategy. And we hope with the Lytec technology that we can bring added benefit to patients.
24:43 Speaker 01 Well, thank you so much for joining me today on Journal Club. I really enjoyed our discussion and I'm so excited to see what comes out of this research.
24:51 Speaker 02 Thank you.
24:52 Speaker 01 And that's a wrap for the first episode of Journal Club. If you enjoyed this episode, please subscribe, rate and review wherever you listen to podcasts. And to learn more about how biology is technology, subscribe to our newsletter at a16z.com/newsletters.
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