Read the Full Video Transcript

Robert Flavell: Hello. Thank you very much to the organizers for the invitation. I'm Rob Flavell from University of California in San Francisco. Here are my disclosures.

I'm going to start by recapping some of the prior discussion with some clinical anecdotes from patients referred last week. We spent a lot of our time in this meeting discussing our patients who are responding well to PSMA-targeted radioligand therapy. For example, this patient here on the left side of the screen demonstrates intense uptake in lymph nodes and bone metastases. These patients typically have more favorable response to PSMA-targeted radiopharmaceutical therapy.

Of course, we also receive these sorts of referrals, people who have low or moderate uptake-- in the case of this patient, with moderate uptake in scattered bone metastases. And then we also see these kind of referrals, patients with frankly PSMA-negative disease. This patient actually has diffuse lung metastases. You can't see them at all in this maximum intensity projection. So these patients with low uptake. This is more common in aggressive variants of prostate cancer, and it suggests a need for new targets beyond PSMA, hence the session.

So there are numerous different formats you could consider for radiopharmaceuticals for imaging and therapy. This is a nice slide I borrowed from Freddy Escorcia from NCI, showing a range of things, ranging from IgGs to small molecules. Of course, we spent the majority of this meeting discussing low-molecular-weight ligands, like Gallium-PSMA-11, DCFPyL, Lutetium-PSMA, et cetera. However, these specific high-affinity peptide or small molecule ligands are not uniformly available, and these are often, in fact, repurposed from endogenous ligands or prior medicinal chemistry efforts.

In contrast, antibodies or antibody fragments may instead be repurposed from biologic therapies-- antibodies, ADCs, CAR-Ts, et cetera. So along these lines, I'm going to focus on three targets, STEAP1, DLL3 and CD46, in this lecture.

Let's start with STEAP1. So this is a transmembrane protein, which is highly expressed on prostate cancer. Its endogenous function is not clear. There are a number of therapies now under development against this target, including ADCs, CAR-Ts, bispecifics, et cetera. One notable example here is the Xaluritamig agent or AMG-509. This is a bispecific CD3-targeted T-cell engager, which demonstrated highly encouraging clinical activity in a phase I dose-escalation study, with the waterfall plots on the right. And similar to other antigens, it's not uniform in terms of its expression, so suggesting potential role for companion biomarkers.

So along these lines, the group at Memorial Sloan-Kettering has previously investigated the Zirconium-89-labeled PET imaging agent. These IgGs have long circulating half-life, require a long-lived isotope like Zirconium-89 for imaging purposes.

So in this study, they used the MSTP 2109A antibody from Genentech. They saw high uptake in tumor lesions. And they did a histologic confirmation study here. I think 16 of 17 patients had lesions positive on PET, and all the sites were histologically positive. These patients actually all underwent treatment with the STEAP1 ADC and they saw actually no correlation between the SUVmax, IHC, survival, and PSA response, although this was a small study, so it might not be conclusive.

Let's switch gears and talk about DLL3. This is a targetable antigen in neuroendocrine cancers. It's short for delta-like ligand 3. It's an inhibitory notch ligand. It gets aberrantly trafficked to the cell surface in high-grade neuroendocrine tumors, including small-cell lung cancer and others. Most of the work on this target, in fact, has been done on small-cell lung cancer, but it is also expressed on neuroendocrine prostate cancer and not commonly in adenocarcinoma.

Therapeutic agents against this target include bispecific T-cell engagers, ADCs, CAR-Ts, and radioligands, now at various stages of development. One nice example of this is, again, from Memorial Sloan-Kettering, from Jason Lewis's lab, where they had the preclinical development of a Zirconium-89 and Lutetium-177-labeled antibody called SC16.

On the right here, you can see some preclinical tumor efficacy studies, where they showed encouraging activity against preclinical neuroendocrine prostate cancer model, as well as, interestingly, they used the same cognate PET imaging agent with the Zirconium-89 labeling to confirm the persistent expression of the target, and then they retreated it in this study.

We also conducted a study on developing Zirconium-89-labeled DLL3 scFv. So in this case, a small low molecular weight antibody fragment. This study was led by Jon Chou back when he was a fellow. And we saw uptake of this particular preclinical agent associated with DLL3 expression and in neuroendocrine prostate cancer. And that was in collaboration with a group at Amgen.

So first-in-human DLL3 PET imaging has been also performed at Memorial Sloan-Kettering. This was recently published. So this is a first-in-human study of 18 patients who had histologically derived neuroendocrine-derived malignancy. The majority of the patients on this study were small-cell lung cancer patients, but there was a subset of four patients with neuroendocrine prostate cancer. Of those four neuroendocrine prostate cancer patients, three of them were positive on the PET scan.

So you can see on the bottom left, we have a patient that had a pretty negative PSMA PET and numerous DLL3 positive lesions. Then in the bottom right, the converse example, very FDG-PET-positive patient with numerous lesions and lesser DLL3.

So the last target I'll talk about is CD46, which is something we've been looking at University of California and San Francisco and elsewhere. So this is an antigen that's highly expressed in prostate and other cancers. There was an antibody named YS5 developed by my collaborator Dr. Bin Liu. This targets a cancer-specific epitope present on this protein. And this got developed into an ADC called FOR46 or FG3246. This data was shown earlier on by Dr. Li, demonstrated some promising clinical activity in phase I dose escalation. And these results were actually just published in the last week.

We've worked on turning this into a radiopharmaceutical imaging and therapy agent using the same antibody. And we performed a preclinical study comparing the Zirconium-89 PET agent to Gallium-PSMA-11-- of course, our standard PSMA PET agent.

Interestingly, we saw that there was uptake across the different patient-derived xenograft models we looked at in this study. And then Gallium-PSMA-11 had good uptake in two of the three models that we tested, but it had low uptake and absent expression in the LTL331R, which was a treatment-emergent neuroendocrine prostate cancer line. We've also been working on developing a radioligand in the preclinical setting.

Just some results from our translational PET imaging study. Here, we've scanned 27 patients now. So I need to stop scanning and start analyzing and writing. So as is typical for these multi-time point for these, I should say, biodistribution dosimetry studies, we conducted multi-time point imaging. We see over time that the antibody clears out of circulation on the initial time point and then starts accumulating in tumors later on. One interesting and incidental finding that we saw is that there is pretty high uptake in the adrenal gland with this tracer in all patients. We don't really know what the mechanism of this is. It was just something we discovered when we started doing the PET imaging agent.

And just some anecdotal examples of a handful of patients across the trial. On the left, we have a patient who's frankly negative on the PET imaging study. The next one over on the right is the first patient I showed you, with mildly positive uptake, and then two patients on the right with more intensely positive disease. So similar to what we've seen in other patients with metastatic prostate cancer, we clearly have some example of antigenic heterogeneity here.

So with this, I'm going to go ahead and wrap up, just to note that there are several emerging antigens in prostate cancer, which can be targeted with radiopharmaceuticals for imaging and therapy. STEAP1, DLL3, and CD46. These all have their treatment niche in different types of prostate cancer.