There's a lot of features that I'll talk about. As you can see here, if you think about the types of therapeutics we have, we already in prostate cancer have radioligand therapy. Lutetium-PSMA-617. We have antibody-drug conjugates being studied. We have bispecifics, and we have CAR T cells. These are what I'm going to focus on during this talk. My first question is, what makes a good drug and a surface target combination? The biology matters a lot. You want to make sure there's expression there, and you want to make sure there's expression throughout the entire disease state. The binding domain really matters. How the antibody internalizes matters. And of course, the payload or the effector matters a lot. Linkage instability, something that we need to think a lot about, is how stable is it in circulation? When does it break apart, if you're an antibody-drug conjugate? And do you get into the tumor well? Do you traffic well? And then how much on-target versus off-target effects are there? Is it breaking apart in the circulation?
And then something we really need to study well are resistance mechanisms. Is the antigen downregulated over time? These key properties, I'm not going to go into great detail because I mentioned a little bit, but I want to focus a little bit about the prostate cancer-specific nuances. We understand that there's lineage plasticity in prostate cancer, and over time there can be development of neuroendocrine disease. Those cell surface targets clearly may change over time. What happens after you give androgen deprivation therapies, and the tumor evolves over time? How much stability is there with that target antigen when you lower testosterone levels? And then, of course, neuroendocrine differentiation I mentioned, and there's heterogeneity. Prostate cancer, as we know, is a very heterogeneous disease, and we can have different expression of different targets in different tumor sites. I'm just going to start with what we know already because this crowd should know very well. We have Lutetium-PSMA-617. And as you can see there, this diagram lays out all the core components. The targeting moiety. Are you going to use a small molecule which might enter into smaller spaces? Are you going to use an antibody that might hang out longer in the circulation? Different side-effect profiles depending upon that? You're going to use an alpha emitter or beta emitter? That might matter as well. The path length bystander effects with a beta emitter with an alpha emitter.
Maybe if you have microscopic disease, that might be better suited for something like that. And then, of course, the importance behind chelator chemistry. How stable is it in the circulation? And there's trade-offs. When you think about engineering these constructs, how much is penetrating into the tumor versus residence time sitting on the receptor? Crossfire effect might be a feature, not an actual bug. And, of course, I think this crowd probably very much supports the idea of studying dosimetry better, not just to the normal organs but in the tumor, and really thinking about how to dose these agents effectively for optimal utilization and to decrease adverse events. And again, one thing to mention is that internalization helps, but it's not strictly required for radioligand therapy. That's something to think about. Now, antibody-drug conjugates. Everything is in the construct. What is the antibody? How fast is it internalized? How well does it internalize? What about the payload? And I think when we think about the payload, I oftentimes hear people talking about the payload like, "Oh, the DAR is really high. The drug-antibody ratio." But I think what's missing here is that just loading more drug onto the construct may not be a good thing. It might lead to more off-target effect there. And how homogeneous or heterogeneous that loading is matters as well.
The linker. The linker is critical. How cleavable is that linker? Does it break apart? Is it physiologic mechanisms, or is it a non-cleavable linker that requires internalization and maybe a low pH before it really breaks apart? And here's just the diagram showing how these antibody-drug conjugates work. They haven't made prime time in prostate cancer yet, but I will be surprised if they don't, since they're used in multiple different tumor types. For an antibody-drug conjugate, we know that internalization's mandatory, that bystander effect can be either a good thing or a bad thing, and we're still studying resistance mechanisms. Is it really downregulation of the antigen? Are there efflux pumps, lysosomal changes, et cetera? There's a lot of things that could lead to resistance. Now, I'm going to move quickly to bispecific antibodies. And this binds to at least two different targets. You can have trispecific antibodies as well. And the whole idea behind it is that in prostate cancer, what we're focusing on are T-cell engagers. We're bringing a T cell to the tumor or forcing that immune synapse, but it doesn't have to be binding to T cells. You don't have to have cytokine release.
You can bind a couple different tumor-associated antigens. You can bind immune checkpoints and take a couple checkpoints out as well. One thing we're thinking about is gating. That's gotten some popularity. Do you need to bind just one of the two to be activated? Do you need to bind both of them for increased specificity? And there's mask gating now, where you basically have a peptide that's cleaved by the tumor-associated proteases, and it's inactive systemically. Gets to the tumor microenvironment before it's really activated there. I'm just going to show you one example. I'm not going to focus a lot on the drugs at all, but VIR-5500 PSMA was presented by Dr. De Bono at ASCO GU just recently. And this is gated. You can see the diagram on the left there that I borrowed off the internet, but you can see that it requires protease cleavage in the tumor microenvironment. And what you see are pretty good PSA responses there on the right, especially at higher doses, without significant Grade 3 treatment-emergent adverse events, without prophylactic corticosteroids, et cetera. Now, I'm going to move on to CAR Ts, and you can see here this is the single-chain variable fragment which takes a small fragment from the heavy chain and the light chain and fuse them together with the peptide to recognize.
The hinge region is really important when you're making a CAR T. It has to be long enough to affect that immune synapse. Flexibility is important to prevent T-cell exhaustion. All these are important components. But then the co-stim molecules, when you think about second-generation, or even loading two co-stim molecules with third-generation CAR Ts. And then finally, the fourth-generation CAR T, which we're working toward, is armoring these CAR Ts with what we are calling trucks now. Obviously, I don't know if Dr. John Lee's in the audience here, but we've been working closely with him, and this is his STEAP1 CAR T, which Jessica Hawley started at our center. The clinical trial. Now, she's at Janssen, or Johnson & Johnson, leading that KLK2 program. But Rosa Nadal is now leading this study, and we're escalating dosages now. You can see the construct on the bottom is nicely devised there. What I want to say is this, is that there's no perfect modality. When you do cross-platform comparisons of these modalities, there are pluses and minuses to each. When you think about the first one on the table, requires internalization, radioligand therapies is plus/minus, but antibody-drug conjugates, yes. Immune engagement. Is there that immune synapse? Certainly for bispecific T-cell engagers and for CAR Ts. Reversibility. Well, RLTs? They degrade over time.
Bispecifics have a short half-life. Antibody-drug conjugate levels go down over time. And then finally, bystander effect. Yes, certainly for RLTs. Sometimes for ADCs. Manufacturing complexity, of course, is the highest for CAR T-cells, but these are all considerations. There's no one that necessarily wins in all situations. I just want to talk quickly about PC-SYNERGY. We all know Felix Feng who started this. Of course, many of you in the audience may be on this photo that you can't see very well, but this is something we need to work towards. We need to understand the heterogeneity of expression, and we need to get specimens to understand what happens after treatment response and resistance to the expression of these tumor-associated antigens, and that's what PC-SYNERGY's focusing on. I just want to wrap up and summarize saying there's a lot of new cell surface targets in prostate cancer beyond androgen receptor and PSMA. I listed a bunch of them there and all four of the modalities that we're using right now. Different characteristics in the modalities emphasize there's no one-size-fits-all. And although radioligand therapy is the only modality that's made prime time, certainly there's more to come, and now is the time to study phenotypic heterogeneity in prostate cancer because it's certainly going to have a role in treatment resistance. Thank you very much.