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John Lee: Hi, my name is John Lee. I'm here at UCLA, and happy to talk about the role of antibody-drug conjugates in prostate cancer. These are my disclosures. They don't relate to anything I'm going to talk about today.

So just to give a very brief 30,000 view of antibody-drug conjugates, these are molecules that are constructed with a binding moiety, usually an antibody or antibody fragment. And to that is conjugated a chemical linker and a cytotoxic payload. And the whole idea is to really enhance the delivery of cytotoxic payloads to tumor cells while sparing normal tissues.

And so clearly, this is an area of very significant development in oncology. 13 ADCs are currently FDA approved. About 100 ADCs are currently under clinical investigation. Yet, no ADCs have been clinically approved in prostate cancer. And certainly, that isn't related to a lack of trying.

So there have been multiple failures of ADC programs in advanced prostate cancer. This is a table that I took from a publication in 2023. And you can see that there are a number of very well qualified targets, including PSMA, Trop-2, STEAP-1, tissue factor, and DLL-3.

And in the early phase trials, usually phase I trials, the problem was that they couldn't achieve really a good therapeutic window. So you would see fairly low overall response rates, usually around 10% or less. And a failure to dose escalate beyond those levels due to toxicities.

And certainly, this is just kind of hot off the press. We're very excited about a B7-H3 ADC that MacroGenics was developing. And just a couple of days ago, after seeing the phase II data in prostate cancer, MacroGenics actually pulled the plug on Vobra Duo. And so this is one of the very promising programs that we were thinking were going to move forward, but unfortunately not.

However, there are still reasons for cautious optimism. And so, for instance, there's this agent, ARX-517, originally a molecule that was developed by Ambrx, purchased by J&J, that targets PSMA. This constitutes a human J591 binder. There is site-specific conjugation of a stable PEG linker and an Auristatin derivative payload.

And in early results from the phase I/II APEX-01 study presented at ESMO 2023, you can see from these waterfall plots that there were significant reductions in PSA that were observed, as well as radiographic responses. And so we're awaiting the results of more mature data. But another reason for cautious optimism would be FOR46 which targets CD46.

This constitutes a fully human binder, non-site specific conjugation, MC-vc-PAB cleavable linker, and MMAE payload. And the phase I results were just published in JCO a couple of days ago. And you can see again from the waterfall plots, looking at radiographic responses as well as PSA responses, that there are a subset of patients or a significant subset of patients that actually responded during this phase I dose escalation.

So there are certainly many challenges to the effective application of ADC therapies in metastatic prostate cancer. One of these is antigen heterogeneity. And certainly from my lab, we've gone ahead and published some studies where we look, for instance, at relative expression of PSMA versus STEAP-1 in the University of Washington, a rapid autopsy program.

And what we really appreciated was the degree of heterogeneity that was seen in PSMA relative to what was appreciated with STEAP-1. STEAP-1 being preserved in a higher proportion of patients across metastases, whereas that was significantly lower with PSMA. And certainly, we saw patients that demonstrated no PSMA expression in their metastatic sites.

So other challenges to ADC therapy in advanced prostate cancer relate to low tumor penetration, off-target toxicities. Certainly, the potential for drug resistance to the payloads that we utilize. And then the need to develop novel payloads. And then also, optimize linkers associated with these payloads.

And so next generation ADCs are quite interesting. So this is a little bit of a busy slide. But on the left side, you see the types of innovations that are occurring. So certainly, you can consider utilizing different payloads or next generation payloads, including those that might act as protein degraders, immuno activators.

Or you could even consider conjugating on multiple payloads, so considering multi-drug payloads within a single molecule. Certainly, on the antibody side and delivery side, you can also consider using bispecific antibodies to target more than one target antigen. And you can make other modifications to the antibodies themselves.

So really, I just wanted to focus on the new payloads. Certainly, there are multiple classes of these payloads going beyond just microtubule inhibitors as well as DNA damaging agents. Certainly, there's very significant interest in antibody engineering to allow for multi-antigen targeting, as well as dual payload designs.

And pertinent to prostate cancer, there is a dual antigen targeting ADC developed by AbbVie, which is this ABBV reagent shown here in the bottom right, that targets both STEAP-1 and PSMA. And that's actually in a phase I clinical trial currently.

So I just wanted to end with a couple of notes about what we're doing in the laboratory to try and overcome this issue with therapeutic window. We certainly believe that if we can identify synergistic payloads that are active in prostate cancer, we might be able to then utilize these in future ADC designs.

And so a PCF Young Investigator in my laboratory Galina Semenova has actually conducted a dual payload synergy screen utilizing a number of currently available payloads but also next generation payloads. And what she's identified is several combinations that appear to be synergistic from the screen. I'm just going to highlight one, which is the combination of genotoxic agents and BCL-XL inhibitors. And she's gone ahead and validated this across a number of cell lines.

And we can see is that if you look at the combination index of combining, again, DNA damaging inhibitors and BCL-XL inhibitors, the combination index is less than 1 across all of these cell lines, really indicating that this holds true across a number of prostate cancer models. And so I'm not showing the data today. But essentially, she's gone ahead and demonstrated with an in vivo model. So if you combine this in the context of ADCs that indeed in vivo, you see synergistic activity as well.

So I'm going to end with looking at the expanding landscape of potential targets in advanced prostate cancer. So a couple of years ago, this figure came out basically summarizing the antigens that are targeted by active ADCs that are under clinical investigation. So those targeting PSMAs, STEAP-1, CD46, B7-H3, and TROP2. But certainly, there are many others in development, including those targeting DLL3, tissue factor, CEACAM5, PSA. And I think this number will continue to grow on a yearly basis.

But what's going to be very important is really profiling the expression and co-expression of these cell surface antigens as they're validated and licensed. So this is some of the work that we're doing. We're doing immunofluorescence analysis on many of these rapid autopsy specimens to really characterize not only at a tumor scale, but also at a digital level, what the co-expression of these cell surface antigens is, as this is certainly going to be relevant to combination therapies as well as these combination engineering strategies. So I'm going to end there. And thank you for your time.