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Martin Pomper: It's a tremendous honor and pleasure to be able to talk about some of the early history of PSMA. Let me see if I can-- so some disclosures. So the story begins in the laboratory of Julius Horoszewicz, who initially isolated the LNCaP cell line. And he and Gerald Murphy characterized that cell line. And then they went on ultimately to produce antibodies against that, which became PSMA. That was back in the '80s.

A few years later, Skip Heston cloned a cDNA-encoding PSMA. And from that, we learned that it was a type II integral membrane protein and that it also had a significant sequence homology with the transferrin receptor. Now, back in those remote days, I was a graduate/medical student at Illinois developing imaging agents for breast cancer.

But I was also interested in imaging dementia. And to do that, I felt that there was something about glutamate that was underlying a lot of neuropsychiatric disease and dementia. So I was interested in being able to image and potentially inactivate an enzyme called phosphate-activated glutaminase, which provided the majority, the lion's share, of neurotransmitter glutamate in the brain.

But this was something that I presented to the chemistry department as part of a course that I took. I couldn't really pursue it, had to finish medical and graduate school, had to go on to residency. So then by 1996, I was now a newly minted neuroradiologist at Johns Hopkins, an assistant professor. And I came across this article, still interested in glutamate.

And here, you could see a different enzyme that produces glutamate, the enzyme known as NAALADase. And in this article, they had some inhibitors that actually inhibited NAALADase. That I thought if we could radiolabel them with positron-emitting agents, we could get a sense of what's happening in the brain with glutamatergic transmission.

The trouble is that those compounds were all very hydrophilic. They looked a lot like NAAG. They were phosphinic acids. They weren't going to get across the blood-brain barrier. So I put this on a back burner a little bit until, at roughly the same time, I saw this article by Joe Coyle. And here, he showed that that NAALADase enzyme was the same thing as PSMA.

So although there may be a blood-brain barrier, there's not much of a blood-prostate barrier. So I said, well, to heck with the brain. And let's start thinking about prostate cancer. So I started revisiting some of those small molecule agents.

Now, at the time, there was a product, ProstaScint, based on the 7E11-C5 antibody that binds to an internal epitope. But this product wasn't used much because it didn't give very visually appealing images. It wasn't very high sensitivity. You had to wait nearly a week to image after you injected it.

So having been a chemist focusing on small molecules and training a little bit in PET with Mike Welch at Wash U, I thought that we had an opening here and there was an unmet need for something with better pharmacokinetics, like a small molecule, for imaging and treating prostate cancer. So like any assistant professor, I started to try to get funding. And I wrote a grant to the Department of Defense. And I thought it was a really nice idea.

But the CDMRP begged to differ. So they had a different attitude. But still, I felt this was really still a good idea. But meanwhile, at around the same time, Neil Bander was focusing on the antibody aspects of PSMA. And he recognized not only the importance of the target but also of having an antibody that bound to an external epitope, which was the J591 antibody. He also showed that PSMA is present in tumor vascular endothelium, suggesting that it might actually be a pan-cancer target, so lending further importance to the target.

So by the late '90s--1999--there was a chemist named Alan Kozikowski at Georgetown. He was coming up coincidentally just to visit Johns Hopkins pharmacology. I also had an appointment in pharmacology. And I met with him, and he asked me what I was working on. And I told him I was looking at NAALADase inhibitors for prostate cancer. And he said he had what he called NAAG peptidase inhibitors as neuroprotectants.

So I said, ah, why don't--if you have some good compounds, maybe I could take those, derivatize them for imaging, and we could maybe pivot to prostate cancer. So I got this thiol, which is very easy to label with carbon 11. And our PET center is big on carbon 11. We then tested it by doing blocking studies in murine mouse kidney, as well as non-human primate kidney, because I didn't have any access to prostate cancer cells. But as you know, there's a lot of PSMA in kidney.

And we did show specific binding. So we had a specific agent that bound PSMA that could be used for imaging. And then you switch out the isotope, and it could be used for therapy. Only a few years later did I show that you could actually look at cancer itself directly.

So we wrote a number of papers back then, in the early 2000s, and eventually focusing mainly on halogens. But we were also interested in radio metals. So we found that by doing computational docking as well as by earlier co-crystallization studies between our earlier compounds and PSMA itself, that we needed a 20-angstrom linker between the chelator and the affinity agent to get productive binding to PSMA.

We also showed that not by using the radioactive version of rhenium, but by using rhenium 185 and the bisquinoline tricarbonyl version of the chelator, that we had a fluorescent agent. So we were able to show in this paper that the small molecules, just like the antibodies, were able to be internalized, which made us feel that this was going to be a very nice target also for therapy.

We then went on to make some gallium agents, like shown here on the upper left-hand corner. And others made gallium agents. On the right is the HBED-CC chelator from the famous PSMA-11 that's used here and around the world.

John Babich gave me this image in real time what had happened, probably a couple years before 2013. Thank you, John, because I've shown this many, many times. But this was the first time a human being was imaged with a PSMA-targeting radiopharmaceutical. It was a SPECT study.

Another big advance was, of course, PSMA-617. Through a surprisingly brief medicinal chemistry campaign, PSMA-617 was generated by the group at Heidelberg. Very nice PK. And in fact, I'm going to touch upon this again in my talk that I have tomorrow. But most famously, labeled with lutetium 177, you can see that the cancer melts away.

I think that everyone's probably seen this image. Jonathan Simons, the former CEO of the PCF, he was very excited when Michael Hofman showed him this. So he showed it to me. And on the right side of the slide, you could see a patient whose quality of life is vastly improved by this.

But in addition to quality of life, Oliver Sartor showed in the registration trial that it's actually life-prolonging therapy. Now, the only issue for me, I was--truth told--a little bit disappointed. It was only four months. Given how stunning the images were, that all that cancer was gone, still only four months. So I think now we just have to focus on more different isotopes, affinity platforms, and rational combinations, which we'll be hearing about today and tomorrow, so that the Kaplan-Meier curve could look a little bit more like that, which is our ultimate goal.

The good news is that there's so much interest now in molecular radiotherapy. And I've been thinking about this stuff for over 40 years. But I have never seen so much interest as now. And thankfully, these aren't all PSMA targets. So hopefully, within these different shapes you see here, we have the rudiments of a cure to some of the most devastating diseases of our time.