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Scott Tagawa: All right. Thanks for the invitation. I'm going to shift gears a little bit. Still PSMA, but I'm going to talk about antibodies. I'm going to take a minute to tell you—I don't have an outline, so I'm going to show a couple slides of what I'm not going to talk about as a kind of a teaser for the afternoon session.

So antibody-drug conjugates. One of these is not an antibody. But there's three with J591. I'm going to come back to that. You'll hear about this afternoon, I think right after lunch. And then the other mechanism besides chemo is the immune system.

So there's CAR-T cells and a number of bispecifics that you'll hear about from Dr. Dorff a little bit later. So that's my teaser because the title I was given initially was "overall antibodies." So this is a list that continues to grow, and I'm going to need a second slide. But as many of you will know, several of these use antibodies. So this is what I'm really going to talk about.

Antibodies—largely because of size differences, not only size differences, but largely, I would say, because they're antibodies—have to do with size leading to differences in both kinetics and biodistribution. You can see on the top right, some images from a couple of studies with Mike Morris and others.

And you can see that those are measured in days versus, as you all know, measured in hours with the small molecules. That's in terms of how long they circulate, as well as where they land. What made sense—so we took a look at—a post hoc look at a number of patients that were treated across prospective clinical trials.

And this was not surprising at all. More marrow expression with the—this is all lutetium—more myelosuppression with the antibody, more dry mouth and nausea from the small molecule. We updated the dataset with another 45 patients and saw very similar things.

One of the things that we looked at in the updated dataset was transaminitis, and that didn’t look to be so different. Going back to the PET images of J591, you can clearly see the liver a lot there. But luckily, that didn’t pan out, at least in short-term follow-up.

OK, single slide with the beta J591. So one extreme study, the rest lutetium. And this is all published, so I'm not going to spend a whole lot of time on it. But I think a couple of the keys are—one is what we've called fractionated dose.

Some people call it dose-intense, some people call it one and two cycles close together. We call it a single fractionated dose. But it looked to be interesting data. And that formed the basis that I'll show you in a little bit for the PROSPECT trial.

And then our first randomized trial was what I’ll call low-volume mCRPC, not evidence of metastatic disease on CT and bone scan, where there was a delay in the development of metastasis visible on CT and bone scan. That was lutetium versus indium.

And as was seen yesterday, I think a couple of times, so I'm not going to spend too much time on this. In the same kind of disease state as before and SPLASH and ECLIPSE, but using the antibody in this dose-dense fractionated cycle with best standard of care that includes docetaxel.

That is sequential, not concurrent. Although in that long history slide, we did do a study that showed that lutetium-J591 can be given concurrent with docetaxel. OK. So many of you have seen this publication, so I'm not going to belabor it too much. I'm going to spend more time on the not POLLYPS data.

But radiochemistry studies, and then a single administration, escalated activity without an MTD. There was one that had DLT, but no MTD at the highest dose. So we said, OK, the recommended phase II dose, single administration, was 93.3 mCi, because we decided not to continue with a higher injected activity.

Some of you have seen this, some of you have not. So this was basically two separate trials within one. So a fractionated dose, one—so the same day 1 and day 15, except this time with actinium-J591. And then multiple cycles, kind of a typical every six-week schedule, looking to establish a recommended phase II dose and preliminary activity.

What you will see is the typical definitions of dose-limiting toxicity, except we also included any grade adverse events that would delay another cycle up to cycle 3 in the multiple-dose cohort. So this is the different levels of injected activity that we’d administered.

And you can see some preliminary efficacy data with the PSA waterfalls. So we came up with a recommended phase II dose in this fractionated dose schema. We did not with the—basically, what we decided was that we don’t recommend this drug at six-week intervals.

And you can see here that unlike many other dose escalation trials, you see grade 1 dose-limiting toxicity. And that's because it delayed cycle 3. So my experience in terms of chemotherapy—you give a growth factor, you stimulate the marrow, you give chemotherapy—that’s no good.

I think giving radiation to a recovering marrow is probably not so good. So I'm going to come back to that administration, because eight weeks looked to be OK. A bunch of preclinical data—I think some of you have seen this—on the internalization and retention of small molecules, at least PSMA-I&T and PSMA-617, with or without the antibody. I think this is kind of interesting.

We took the leap and did that antibody–small molecule approach, but also with alpha–beta. And you can see this was done at eight-week intervals, and it looked to be safe. So we came up with what we decided was a recommended phase II dose of this combination at eight-week intervals. So I think that is one of the keys for this.

With some preliminary results—this was from ASCO 2023, and then updated last month at ASCO GU, where we could calculate a median overall survival. Because the initial presentation was right after we found the recommended phase II dose.

And like many other mechanisms out there, can we add immune checkpoint inhibitors? So you can see on the left, hopefully at least one of these is true. Maybe all is true. Who knows. But the rationale for this kind of combination.

And like the UCSF data, essentially, a single priming dose. So if we believe that radiation does lead to the potential for an abscopal effect, or at least make immune checkpoint inhibitors work better, that's basically what we did. Phase I has been presented, where three of—I don’t know if this was luck.

None of them had MMR, but three out of six had a prolonged response. So we'll see what happens in the randomized portion of this trial, which is ongoing. This—as many of you know—this drug has been turned over to Convergent.

And this is their schema for their phase II trial. Also includes a look at different activities. And then I'm not showing you the first version of this radiolabeled antibody because I haven’t seen it with thorium-227, other than the fact that it didn’t look like it worked too well or was not safe. I'm not sure why—it was the long half-life.

But this has now gone forward. So the preclinical publication you can see here, I’d say one of the interesting factors is using micropa in terms of conjugation. And that, preclinically, looked to be better. But now, they’re going forward with actinium, which is now in human trials.

So in summary, actually the field started with antibodies, with J7011, which I didn’t show you. Both antibodies, as well as small molecules, can accurately target disease. And I think there’s a place for both. I personally think there’s interesting data with the combination. So thank you very much.