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Ray De Chaisse

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2020-09-27

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2020-09-27

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1. “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 LITEC technology that we can bring added benefit to patients.”

   2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

2. “And I think that then hints to a broader universe of lie tact that target different receptors that are tissue specific in different settings. That's the tip of hopefully a big iceberg of interesting new degraders.”

   2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

3. “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. That's really a critical molecule. You could get wrinkles, God forbid. Yeah, 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 strength to this approach”

   2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

4. “That might otherwise have been blockers. We're now converting them to degraders through the LiTAC approach. Another dimension that we're expanding upon is the lysosomal trafficking receptor that we hijack. So the Mandos 6 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 LITAC family are targeting a receptor called the Acyalloglycoprotein receptor which is a liver specific lysosomal trafficking receptor. And we have a preprint that we posted on Chem Archive on this new generation of LITAX.”

   2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

5. “So, this was the version 1.0 of the LITAC 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 LITAX 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 nanosix phosphate groups. And with our new chemistries, we can make different geometries of LITAX 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 rule books. And in the publication, the LITAX, we made are built from these known antibodies. We are now developing LITAX from other kinds of binders, including small molecules.”

   2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

6. “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. you know, that's hard to think about how to drug that, you know, at least at the end point of the disease where you have this material that you really just want to degrade. And so again, I think Eli Tax strategy would be interesting to test in that setting.”

   2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

7. “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 LITAC 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 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.”

   2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

8. “And 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 LITAC sounds like a perfect match between disease physiology and drug modality.”

   2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

9. “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 LITAC 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 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 light approach could be interesting in that setting.”

   2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

10. “We're now exploring therapeutic applications of the LITEC 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 can 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 conditions like Alzheimer's disease, Parkinson's disease. It's been very difficult to figure out, you know, how do you get rid of these protein aggregates that are pathogenic in the extracellular”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

11. “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. EGFR binds its ligand, the epidermal growth factor, and the consequence of that is that triggers a signaling cascade. 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 LITAC approach and some components of that signaling machinery come down with it, that is actually a direct hit, I would say, that's 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.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

12. “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 be more potent than the inhibitor in an axis of biology. I think the degrader can have more axes of an effect.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

13. “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 lite. 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.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

14. “So you need a binding molecule that is very specific and ideally also very high affinity against your target of interest. And 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 lie tag out of a human drug called Satuximab. It's an antibody against EGFR that is used, you know, in the oncology setting. That process of taking an antibody against a target and just decorating the antibody.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

15. “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?”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

16. “And one of the best known lysosomal trafficking receptors is the so-called MANOS-6-phosphate receptor. And Manose 6 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 Manosix phosphate receptor.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

17. “Right. So nature has already come up with a way to degrade the proteins that our membrane associated in extracellular. And you just developed a mechanism that allowed you to say which protein you want to degrade and then extracting it from the extracellular space and degrading it inside the cell.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

18. “Receptor system. So that's the key 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 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 LITAP. Binder on one side for the target, a binder on the other side for a lysosomal trafficking receptor.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

19. “So again, how does 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 hydrolases within the lysosome. 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”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

20. “It's kind of like pharmacodynamics 101 that you have a reversible inhibitor and you're going to have this equilibrium. But 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-op this endogenous pathway the ubiquit and proteosome pathway but they can't reach these proteins outside the cell so what cellular pathway did you co-opt to degrade those proteins”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

21. “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 and 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, and that has now been borne out, even in some early stage human clinical studies with protax. The same could very well be true with lie tax. Of course, it's a much earlier technology, so we don't know that definitively, but there's, I think,”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

22. “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 sulfurous molecules that have been successfully drugged with monoclonal antibodies, you might actually do better if you convert over to a degradation strategy.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

23. “I see. So the pro tags 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.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

24. “Cancer immune evasion, for example. And many of the molecules we wanted to drug were really not drugable using the conventional blockers. And that's where the lysosome targeting chimera liec research started.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

25. “Meanwhile, there's this whole other world of proteins which are outside the cell. So these are proteins that are displayed on the cell 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 proteasome. And as well, there are many proteins that are just completely secreted by the cell and just released into the extracellular space. 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”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

26. “Well, the targeted degradation field began with the protax, 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.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

27. “So, you're using the endogenous mechanism that the cell already has for flagging 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 a really nice pocket that could be targeted with an activity inhibitor. Right. So what are some of the limitations of these approaches?”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

28. “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 up drug and it would block the function. So the cool thing about these protects 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 protack or the targeted degradation approach expands the druggable proteome because now more proteins can be drugged because you have this other way of doing it through degradation and not just blocking.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

29. “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 ubiquitous and proteosome 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. What a protag 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 ubiquiting tag, adds the flag. And then that brings it to the proteasome to be degraded.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

30. “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 De Chaise realized is that you could build a molecule that artificially bridges the gap between a target protein and this ubiquitous machinery. And with that molecule, you could basically get a protein ubiquinated intentionally and therefore degraded. So that was their conceptual idea.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

31. “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 De Chaise, who at the time was at Caltech. Now he leads research at Amgen. And they have 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. 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”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

32. “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”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

33. “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.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source

34. “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.”

    2020-09-27 · a16z Podcast · Degrading Drugs for Problem Proteins: Journal Club now on Bio Eats World (ep 2) · IDENTIFIED FROM THE TRANSCRIPT · source