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Oliver Sartor: Hi. I'm Dr. Oliver Sartor and I'm here with you today. And we do have a special guest, Anna Wu, who is chair of immunology and theranostics at City of Hope and co-founder of ImaginAB. So welcome Anna.

Anna Wu: Thank you. It's great to be able to be here today and have a chat with you.

Oliver Sartor: Yeah. So we're going to talk about a couple of things. And gosh, you have done some really amazing work. And I'm going to start out by asking just something that I'm curious about. You have figured out how to image some of the immune system.

And I'm just curious if you could explain that, what you're doing about imaging the immune system to both me and our listeners, and then I'll just follow up with whatever questions might come in my mind.

Anna Wu: Sure, I'd be happy to. I think the thing to point out is we're trying to image specific subsets of immune cells that have important roles in disease. And for example, one is the T lymphocytes that express a cell surface marker called CD8, because those CD8 T cells are the actual killer cells that are very active in cancer immunotherapies, but they're also active in other processes, autoimmune processes, et cetera.

And it's important to note that CD8 and many of the ways we define these immune cells or identify them is through cell surface markers, which have corresponding antibodies. So for years, for decades, immunologists have worked to classify—identify, classify B cell types and these cell surface markers.

And they use antibodies as their tools to distinguish these cells. And as you probably know, although maybe not everybody listening knows, one of the things that we specialized in is the ability to use antibodies for imaging agents and also for targeted radionuclide therapy.

And so we had worked on an antibody platform, specifically using engineered fragments that are really optimized for radionuclide delivery. We could talk about those a little more later. But a platform, for example, called the minibody.

And along the way, as immunotherapies became more effective, but also as our clinical friends started to see challenges in using conventional imaging, including FDG-PET, to try to monitor these immune responses, we realized that beyond just imaging glucose metabolism with FDG, we could actually try to use this antibody-based approach to look specifically for certain types of immune cells.

So that's what we did. First in mice, but more recently in patients. So we're very excited that we've really been able to show conceptually that we're able to image a very important class of immune cells, the CD8 cytotoxic lymphocytes, using this approach.

Oliver Sartor: Anna, I was fascinated when I saw in one of your manuscripts that you could actually image the tumors even before the immunotherapy. And I wonder if you could elaborate on that a little bit about how these tumors manage to aggregate the CD8 cells, so you can see them in the body.

Anna Wu: Well, I think that touches on a really key question in cancer biology, which is that normally in a healthy individual, we would think that the immune system can recognize cancer cells and kill them.

But instead, tumors arise in that environment and they're able to evade or thwart the immune system, but it doesn't mean those cells aren't there. And we build on, again, years and decades of work from surgeons and pathologists who've taken tumors out of patients and stained and looked on slides and seen these immune cells, they might be there or they might not be there.

So we've had a lot of hints and a lot of knowledge about the fact that these immune cells might or might not be there and they might or might not be active. But we've been limited to doing biopsies. So we've known that the immune system plays—can play—an important role in responses to cancer.

But the goal on our part, as imagers, as molecular imagers, as nuclear medicine specialists has been, can we now develop radiotracers to do this on a noninvasive whole body level? Because also, as we know, tumors can be very heterogeneous lesion to lesion in terms of what they're expressing, what their metabolism is, what their biology and their potential is.

And likewise, the state of the immune system can be different lesion to lesion in different patients or different diseases, et cetera, before and after treatment, which I think is especially interesting because now we have immunotherapies and we'd love to look prior to treatment and following treatment to understand—if we look before treatment, can we somehow identify features that would help us understand predictive markers, whether a patient might or might not respond to a specific immunotherapy?

And I think just as important once they're on therapy, is it actually working? Should we keep going? Should we change therapy? Should we add something else? So I think what I would say is we're building on—we're standing on the shoulders of giants in terms of identifying not just the immune cells, but also a lot of work on tumor immunology.

But what we've done now as imagers is to focus on, how can we develop noninvasive whole body methods for seeing the entire immune system in action? Because we know there's heterogeneity there. We know we need to understand it.

Oliver Sartor: It's really amazing because we've been doing these tumor-directed biopsies and analysis for so long. But I think you're the first person to really think about this in a theranostic sense, to bring imaging into the fore for the immune system, both before and after therapy. Now, am I giving you too much credit or is that the proper amount of credit?

Anna Wu: I think we're probably the farthest ahead in looking at this subset of cells. But people have been—I would say people in the field have realized the importance of being able to image the immune system.

So I have to give credit to groups in the Netherlands, such as Elisabeth de Vries, who took some of the actual immunotherapy drugs, like the checkpoint inhibitors—anti-PD-1, anti-PD-L1 antibodies—and labeled those and put those into patients to see where they're going.

And we can even actually go back a long way—I'm sorry, I can't remember—I remember specific images in my mind, but not specific papers, where people would label things such as anti-CD3, OKT3 antibody, and image inflamed joints and arthritis.

So that concept has been around for a time. I think Alberto Signori in Italy is one of the ones that was an early pioneer in this area. But I hate to mention too many names, because there really are a lot of people who have thought, on and off about, gee, it'd be really cool if we could image inflammation, image immune responses.

I think what triggered this was the advances in cancer immunotherapy and the checkpoint inhibitor drugs. And then the realization that the tools we have are good, but maybe we need some more specific and better tools to image, so that we can treat more appropriately.

Oliver Sartor: Now I've seen the CD8. Are there other targets that you're particularly interested in imaging? Or is that something you can share right now or rather not? I'm not trying to get proprietary information.

Anna Wu: It's not proprietary. I mean, there are a lot of people working in this field. There are numerous groups and companies even doing CD8 imaging agents. So we're not alone in the field. I think a lot of people are interested in CD4, which is the other major T-cell marker.

CD4 is challenging because there are a lot of different flavors of CD4 T-cells. And some are helpers and some are regulatory and suppressors. And just by imaging CD4, we can't tell the difference. So that's where it gets a little more complicated.

If you have a disease or condition where your response is predominantly helper or predominantly regulatory CD4s, then that's a setting—a specific setting—in which CD4 imaging could be very useful. But it's not as clear cut how to use CD4 imaging, although I think there's certainly applications for that.

But people are also looking at other cell types. Monocytes, macrophages play important roles. The innate immune cells, the immunosuppressive immune cells, as well as the effector cells. So, unfortunately, the immune system is very complex.

And that actually complicates the imaging too, because there's so many cell types involved. And it's what they're doing in combination. Sometimes that's just as important as—and I think it's true actually in general for cancer imaging, with the exception of FDG.

No one marker is going to tell you everything you need to know. So we have to find the more useful ones and figure out how to use, say, a couple of orthogonal markers perhaps to really understand what's going on.

So it's a complex business, but there are many laboratories, many people working on different aspects of immune and inflammation imaging. So I'm not going to stand there and say, oh, we're the first. I think that we're at the front in terms of trying to push this forward, realizing how important and how useful it could be. So I'm happy to be in the thick of the forefront, shall we say.

Oliver Sartor: Well, I'm going to say you're in the thick. Now, let's move on to ImaginAB, just for a moment. You're co-founder of ImaginAB, and I wonder if you might be able to give some overall strategies for the company. In broad terms, what are you focused on right now? Again, not trying to get anything proprietary, but just help our listeners understand ImaginAB a little bit more.

Anna Wu: Yeah, I'd be actually happy to, because one of the things I learned in academia was that you can only get so far on an NIH grant. And at some point, if you've got interesting ideas and you really want to translate them, and ultimately, if they're to be able to make them available to broader populations, you have to find a commercial partner, a commercial route.

And at the time we founded ImaginAB, which was a long time ago, there really was not an appetite or understanding of strict, radioactive imaging agents as a potential product, because—I'm talking about the worst kind of product you can make, especially the ones that we're making because we're doing antibodies.

So it's a biological. It's not a small molecule or peptide. So it's expensive to produce, or at least the perception is it's expensive to produce. It's radioactive. So it's got a very short shelf life. You've got to make it and use it. So you've got all those supply chain issues. It's biological. So you can't do things like freeze it or dry it or anything.

And it's only a diagnostic. So the return on investment, the reimbursement is not going to be the same as for a therapeutic agent. So I think we finally—my co-founders are Chris Behrenbruch and Rob Rod. We're three UCLA professors. We look at each other and said, nobody's going to fund this. I think we have to do it ourselves.

So that's how ImaginAB got started. And we originally focused on using some of these engineered antibody fragments that my lab had come up with that are really optimized for radionuclide delivery. They target fast and they clear fast.

So you can image early. On the therapy side, you can reduce exposure to the bone marrow and hopefully overall increase your therapeutic efficacy. And so our original goal was, we actually picked up on three different unmet needs in cancer imaging—three different potential unmet needs.

But along the way, we also realized that the immune cell imaging could also be very, very useful. So in a way, we bet the company and reinvented ourselves and put—ImaginAB put pretty much almost all of their effort into the CD8 imaging, which is completed phase II.

It's moving along. We're waiting for the outcomes readout on the phase II. The phase IIa was complete, where we tried to look at a correlation between the CD8 PET signal and immunohistochemistry paired biopsies. So that work is complete.

And then the final question in the phase II was, does the pretreatment CD8 image that we talked about earlier or the early on treatment CD8 image—patients are going on to standard of care immunotherapy—does either image tell us something important? Or does the delta, the change between the two, is that telling us something important?

So very excited to be in the process of medicals and are now just waiting for outcomes and analyzing the data to see where we stand with that. So that's been very exciting. But I think also, and we've seen it in the field, the excitement, the renewed excitement over therapy using targeted radionuclide delivery has just been incredible.

And I have to say, going back to when I first started working at the City of Hope, a long, long time ago, we were doing theranostics 30, 40 years ago. We had anti-CEA antibodies that were first mouse antibodies and then chimeric and then humanized.

But we would image patients first using indium-111, before PET really became big. And then we would treat them with yttrium-90 labeled antibodies. So that really was already the concept of using the same highly targeted antibody-based agent—in this case an antibody-based agent—to image and treat patients based on very specific localization.

And I had actually developed the minibody for therapy, because the biggest problem was potentially a big problem was bone marrow exposure and toxicity, dose limiting toxicity. So I developed the minibody to maintain the rapid high level binding, but also pair it with fast blood clearance and hepatic clearance, not renal.

Because my colleagues at City of Hope who are experts on dosimetry, et cetera, knew that it would be preferable to park a dose in the—unwanted dose in the liver and not the kidneys. So that was like always the plan. And so ImaginAB, really a few years ago, realized that we shouldn't forget the fact that these minibodies, which they've now really optimized—the platform—could be very useful for therapy.

So they started a program and they now have a couple of lead compounds, minibodies that look very promising in mouse models. They've presented this at AACR and other conferences. So there's definitely—it's now two companies in one, the CD8—the immune cell imaging, but also, I think, a promising pipeline in radiopharmaceutical therapy.

Oliver Sartor: Yeah, I love the minibody antibody concept because there's so many things that are not particularly drugable with small molecules, yet the antibodies, which can target, have a prolonged clearance rate and may have bone marrow suppression.

And your mention of the liver's occurrence mechanism over the kidneys' occurrence mechanism, I think, does have some advantages. Can you explain briefly what a minibody is? Because not everybody may know? So we've been tossing this term back and forth. But what is a minibody?

Anna Wu: I thought you'd never ask.

Oliver Sartor: There we go.

Anna Wu: It's an engineered antibody fragment. And what we've done is we've taken the two variable regions of an antibody, because normally intact antibodies have two heavy chains and two light chains. And the heavy and light chain, the variable regions on the end, that's what comes together and provides the specificity.

So what we've done is we've made recombinant proteins where we just keep the variable regions, but fuse them in a single chain variable region. And then when I was thinking about, what do we really need? Well, we just need additional molecular weight. We want bivalent. So that gives us a molecular weight of 60.

But that's still going to clear via the kidneys. So we want extra mass so that you're above the threshold for first pass renal clearance. And we also wanted it to be a dimer. So I kept the bottom of an intact antibody, which is that CH3 domain for added mass for dimerization and kept the hinge because it makes it a covalent molecule.

So it's an engineered antibody fragment. So forget the construction stuff. It's an engineered antibody fragment that is half the size of an intact antibody, but it retains two high-affinity, high-specificity binding sites.

It's an obligate dimer. So we always have the two sides. And I think also of use, especially for the immune cell imaging, is that we don't have the full bottom part of the antibody, which is what binds to—that's the effector part of the antibody.

And we actually don't want any immune effector biological activity. So we just kept the CH3, so it's biologically inert. So half the weight of—half the molecular weight of an intact antibody, targets fast, clears fast, so that when you optimize everything, you have to optimize tumor, liver, kidney, blood, other normal organs. We were hoping to hit that sweet spot, where we can deliver the highest activity to the tumor.

Oliver Sartor: Interesting. And you've been working at this for a long time. I'm going to ask you one more question about the minibodies. And some people are starting to talk about dual targeting. They may have not just one target, but two targets.

They might want to bind, say, PSMA and maybe they want to bind GRPR, as an example, or maybe you want EGFR and MET. Two types of things. Is that something that you think is promising? Are you doing that in your own work? Or is that just like one step too complicated for now?

Anna Wu: Yeah, we've looked at it on and off. I don't have any active programs now in bispecifics, but I certainly think it's something to be looked at, especially given the heterogeneity of expression of antigens and tumors.

So I think to have two different targets is one way around that. So I certainly think it's a viable approach to be explored. And we just need better information. And it depends. If you've got especially heterogeneous and low-abundance targets, that may be a very good way to go.

For example, if half your cells express one target and half express the other, but 3/4 express one or the other, it's like an OR gate. It gives you a higher probability that you're actually going to hit the cell that you're interested in.

It gives you a higher probability that your agent is going to stay in the tumor. The whole avidity effect of having two binding sites, that if one arm lets go, maybe the other arm is still holding on to your target cell or staying in that tumor region.

So I think it's very interesting. And again, it's a concept that's been around for a while. I think it just—all of these ideas take 10 or 20 years to really mature, be optimized, and have a chance to prove themselves in the clinic. So I think there's still plenty more to be written about bispecifics. It's just I can't do everything, so I don't have an active program right now.

Oliver Sartor: Well, it'd be wonderful. You could do everything. That would be masterful. Listen, and we're going to need to wrap up. And I wonder if we just might want to leave our listeners with any final thoughts. You've been at this for a long, long time. Any lessons learned or wisdom that you might be able to impart. Anything that you think our listeners might be interested in hearing.

Anna Wu: Well, just that I am so excited to see radiopharmaceuticals blooming. And I've always been interested in radiopharmaceuticals for a lot of reasons, including the fact that you can find them and you can count them and quantitate them as opposed to some other modalities. And they go away.

So there's something to be said, for—I think that there have been a lot of anticipated surprises with some of the antibody drug conjugates, because some of those drugs don't go away and they stick around and give you toxicities where you don't expect them.

And that the physics is robust in terms of, at least at a macro scale, how much do you need to deliver to get—so get tumor responses. So I guess it's the part of me that's always like the math and physics side that has enamored me to the use of radiopharmaceuticals.

And all I can say is I am just so excited that people have put in the work, stuck it out, put in the 10 or 20 years of work. We have approved products. We have clinical trials in small molecules, peptides, and antibodies.

And I think that I am looking forward to—well, they already are part of the standard of care armamentarium against cancer. And I'm looking forward to—we had Bexxar and Zevalin at one point. I'm looking forward to further progress, especially in the antibody world, because there's so many additional targets that we could address with antibodies to provide options for patients.

I don't think they'll be the cure all. None of our cancer treatments are cure alls by themselves. It's going to be also learning how to use things in combination. Let me just mention one thing that I think is really exciting, but we're just barely scratching the surface, is the whole question of targeted—either external beam or targeted radiation—and how that interacts with the immune system.

So maybe I'll just leave that there. But I think that is a really intriguing area of research, and hopefully, you will get some fruitful information to help us, again, understand how better to do combination therapies with these new tools.

Oliver Sartor: All right. Well, Anna, we're going to need to wrap up. But thank you so much, Anna Wu, Professor and Chair of Immunology and Theranostics at City of Hope, and Co-Founder of ImaginAB. Thank you for being with you today.

Anna Wu: My pleasure. It's great to be able to talk with you and to your audience as well. Thank you.

Oliver Sartor: Great. Thank you, Anna.