Another piece of gold from Chris -
The funny thing about FAP is it's actually a case study in the challenge of radiopharmaceutical development, and it's something that I feel like we're -- again, we pioneered the thinking around,but it's taken a long time for everybody to catch up. And it's as simple as this. a really good imaging agent is not typically a good therapeutic because the goal of an imaging agent is to target and clear very fast. It doesn't mean that you can't get the therapeutic index, you can. And it doesn't mean that you can't get a good safety profile from that.Because clearly, if you're targeting and clearing fast, your non -- your off-target effects are going to be diminished, right? But it is a fallacy to think that just because you have a beautiful imaging agent, that's what we saw with all of the first 4 or 5 FAP molecules that were in patients had a super-fast off rate. The PET images looked amazing because you had a great target to background ratio, but we saw 0 therapeutic efficacy in those patients, like not even just not very good, but nothing. So now with the FAP portfolio, we're in the interesting situation where we have a very fast off rate, low retention time molecule, which gives the most beautiful images. But then you have something that has an engineered retention time.And so what you're starting to see is a lot of the small molecule strategies are adding half-life extenders using avidity approaches, adding albumin binding domains, doing all of these things to slightly prolong half-life so that you have better tumor retention. And to some extent, we started our life at the other end of that spectrum. And now we have great experience with multiple antibodies in patients. We see great potential. But the whole field is now kind of both at bookends is kind of moving into the middle where there's things that have really different pharmacology and where the pharmacology is truthfully better matched to the half-life of the isotopes.In some respects, the first-generation commercial PSMA and even SSRI agents are kind of violating that principle of pharmacokinetic half-life versus isotope half-life. And so now as we get into things like Lead-212, Astatine, alphas, maybe Terbium-161 is going to be one as well, we can start to think much more cleverly about how do you align the pharmacology of a target with the radiation profile of the isotope. And that's why this field is -- that, in a nutshell, is why this field is in its nascency. And the needle is not going to move by having on the imaging side, another small molecule prostate agent or another choose your favorite isotope. Like that's not what's going to move the needle.It's going to be something that's biologically fundamentally different. And then on the therapy side of things, we've got -- we're going to see that explosion of opportunities in that, call it,engineered molecule space that's going to be a better fit for the next-generation isotopes. And that's why this field is so early in its potential.
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