I don't know how many of you know this, but if you think about Pluvicto, Lutathera, Azedra, probably a lot of other therapeutics, but those three were approved.50% of the radioactivity that you inject into the patient is gone by 48 hours and it goes into the toilet. So we're wasting a lot of that drug and a lot of the cost of that drug, and certainly there's no benefit to the patient. So we're looking and we have the data that's Dr. Hoffman presented earlier, the same schematic here. More dose seems to be better in terms of response rates. More dose seems to be better in terms of reduction in tumor volume. We do have current guardrails, which are looking at what the dose is to the marrow. We have to keep an eye on that and also to the kidney. And of course, these things change every once in a while as to what's important and what's not.
Overarching goal in radioligand development is to improve the delivery of cytocidal dose of radiation to all the metastatic cancer lesions. I think when we talk about the inability to cure patients, maybe part of that is that we're not hitting all the tumors that could possibly take up the ligand, whether that's prostate cancer or other diseases. And I would argue that tumor uptake is governed by three coupled processes, exposure time in the blood, controlled largely by albumin binding and blood clearance. The delivery rate to the tumor, this is determined by tumor perfusion. Tumors are poorly perfused and they do have vascular permeability and they have this thing, this EPR effect we all get excited about for things leaking into it. But they don't get a lot of cardiac output, and from a perspective of what you inject into the patient, a lot of it's not going to the tumor.
It's also reliant on the capture efficiency in the tumor, and that really has to determine the target affinity and the binding kinetics, the K-on and the K-off. So there's things here that we can control. We certainly can control the exposure time in the blood by manipulating the pharmacokinetics through albumin binding. And we'll talk a little bit about that. We can also manipulate the target affinity and the K-on and the K-off by medicinal chemistry. We really can't do much about the tumor at the moment.
The isotopes, I'm not going to get into the details of the isotopes, but these are the common ones that have been in clinical trials and certainly part of the approved drugs, Lutetium and Pluvicto and Lutathera. There's a lot of gaining of interest in the alpha emitters and particularly actinium and lead. And again, one has to consider, and I think it's really important. I'll give you an argument in that regard. It's important to match the vector kinetics and the tumor kinetics with the radionuclide half-life. And this is just a simple graphical representation of what I'm... The point I'm trying to make here is the biological half-life in this particular is expressed in multiples of the isotope physical half-life. And so you would hope to get at least, if you're designing a drug to go into a patient that's going to radiate the tissue and make the best use of that isotope that you've chosen. I haven't said which one. You should have at least a multiple, four-fold of what the half-life of the isotope is in order to allow at least 80% of the energy that's inside there's already nuclides to get to the tumor.
And here's an example of Lutetium. So if you have a biological half-life of 640 hours, which about four times the 159 hour half-life of Lutetium, you basically approach about 80% of the possible disintegrations that can go into that tissue. So having something that sits there a lot less is going to give a lot less dose. And I'm probably telling you everything you know, but sometimes we look at these things graphically, it becomes much more clear.
On the other side, since therapeutic index is key, and tumor to kidney ratio is one of the things we're constantly contemplating because everything seems to be excreted, certainly small molecules getting excreted in the kidney or they're getting hung up in the kidney. If you contemplate for a moment, a half-life in the kidney of six hours, SUV in the tumor, SUV in the kidney being identical, then you see here as the biological half-life and the tumor goes up, you actually have better and better tumor to kidney ratios, and that favors the longer lived isotopes.
There's another part of this whole design and contemplation, and Jeremie has a very nice slide where he has every possible chemical entity that you could think about putting an isotope on. I'm really focused really on what's the impact of the size of these molecules. The graph on the left is a diffusion coefficient versus molecular radius, and that is basically telling us that the smaller molecule, the better diffusion. The graphic on the left on the bottom is basically looking at plasma clearance. The smaller the molecule, the faster gets out of the bloodstream. The bigger it is, the longer it hangs around.
And that generates this other, sort of the valley of death curve here, which is work that Dean Wittrup's group has generated over years of working on antibody delivery. And you see that you have very rapid diffusion of small molecules. They'll get into the tissue. You're in the middle somewhere, things aren't actually getting into the tissue, some of it's getting excreted and going to the kidney. And if you have a very long resonance time with large molecules, they're related, you will eventually get uptake. But of course, time is of the essence because we have isotopes decaying. We're always running against the clock, the ice is melting. And we really want to see how, and we've contemplated this in my previous life at Cornell, how do we manipulate the molecule to be a small molecule in every way in terms of diffusivity, but change the pharmacokinetic profile of that molecule. And so trying to just cut to some of the elements here on the right-hand side.
Basically we came up with a scaffold. It's a trifunctional scaffold. We have a tumor-binding domain, a chelator component, and then an albumin-binding domain. And this enables independently, we can change each piece of that. So we can have, and we've published on this years ago, PSMA being the example, we manipulated the PSMA binding affinity, then we changed the chelator, then we changed the albumin binding and the constructs look like this cartoon where the parachute is really the albumin binder to change and slow down the clearance rates.
We actually have a whole library of molecules that we can put on the end of the molecule to change the albumin affinity. These are all reversible. They're not irreversible. If you go too strong on albumin binding, there's a lot of work Sean Chen's group had done where they put Evans Blue on a molecule, basically stays in the blood too long. You basically have essentially created a protein and you're creating a problem for the bone marrow. But here we're able to sample from about a hundred animal to a hundred micromolar affinity to albumin. So we can actually pick the molecules we want, test them, put them on the same construct, and then run the biodistribution studies to understand what that affinity does for tumor uptake and the like.
And here's an example of work that we published several years ago looking at a PSMA construct. So everything within the blue sort of graph paper there is part of a construct where we are only changing the albumin binding group. So for that, we're really not changing the affinity to PSMA. We're obviously not changing the chelate. We're not changing the charge of the chelate with lutetium in it. And you can see as you change the albumin binding affinity, you're going to be changing the tumor uptake of the tumor retention. The weaker albumin binders are on the top and the images, this goes out from one to 144 hours and the stronger ones are on the bottom.
And this has been translated into the clinical studies. We actually ran a study for Bayer using indium-111 versions of various trifunctional constructs. This is just one patient that's been shown at an AACR meeting back in '24 by Sabita Zitzmann. On the left-hand side is a PSMA-11 gallium scan at one hour post-injection. And on the right-hand side is an indium PSMA trillium construct at 24 hours post-injection in the same patient. And on the right-hand side, you see the area under the curve for the concentration in the tumor versus the kidney and the salivary glands.
This is now currently heading... It wasn't clinical trials. I think it was mentioned by Jeremie about the trials that are going on here... But sorry, technician. God, we're going backwards. Actinium-225 PSMA trillium that Bayer has in the clinic, and I believe they're looking to start a rather expansive trial this summer, hopefully.
Can we do this? Can we play this game for other targets? We love FAP. It was a billion dollar, I think Jeremie and he wrote it editorial, the next billion dollar radiopharmaceutical. And of course, other people have shown the hype graphic, so everything's hyped and then it all falls down because we're too early. We don't understand the problems. And so we have beautiful images, but we don't have good retention. So what was, you see it, you treat it, was you see it, you really can't treat it. I know lots of valiant efforts have been put out there, but it is a nice target. It's expressed on this cancer cells in certain cases and on the stroma in many cases and cancers.
And we spent a lot of time trying to manipulate the binding domain. So here instead of playing with the chelate or playing with the albumin binding domain, we're playing with the actual pharmacophore and finally got to a point where we have what looks like subpicomolar affinity on FAP. And this is a biodistribution of Lutetium and a U87 glioma that constitutively expresses FAP. It looks nice in preclinical models. This paper, which just came out in the JNM online at least, this is work that was done in collaboration with Professor Lapa's group at Augsburg Clinic in Germany. And this is a patient with SFT showing uptake of the therapeutic dose at 24, 48 and 160 hours post-injection, showing extremely impressive retention. This study, this compound is now in the clinic here at UCLA and other places. Here we go. I'm just about to wrap up. And so with actinium and soft tissue sarcoma in several centers around the country.
That half-life that we see, it looks like it's actually something like 1,400 hour biological really allows us to take it full advantage of the long half-life of actinium. And I don't have enough time to go into this graphic on the right, but when you have the opportunity to actually match a long resonance time with a long-lived isotope, you can deliver a lot of radioactivity.
In summary, radioligand therapy has currently experienced a dramatic renaissance in oncology. Certainly conference is evidence of that. Successful radioligand therapy requires an optimal therapeutic index to maximize treatment outcomes and also make sure we keep the patient safe. To date, low-molecular-weight ligands have been successfully used for this, but we can improve the outcomes. There was lots of discussion about we're not improving overall survival in our control studies. Let's hope that in the future we'll be able to do that with better drugs. And that long paragraph basically is summarized that we can manipulate the PK and we can manipulate the uptake in the tumor by having a molecule that's possible to manipulate the PK without influencing the binding domain. And radionuclide selection is key and it should be maximized or optimized in order to deliver the best dose based on the resident's time and the tumor.
And as I'd like to thank all my various colleagues around the world that have contributed to all this work from the beginning of the concept to today. Thank you.