Welcome to day one of the Bank of America Healthcare Conference. I'm Greg Harrison, one of the biotech analysts here at B of A. Today we have IGM Biosciences with us. From IGM, we have Fred Schwarzer, Chief Executive Officer. Thanks for joining us, Fred. Thanks for having us. Appreciate it. Maybe you'd like to start off with a couple of opening remarks, then we can jump into Q&A. Sure. I guess I probably would focus on the two most important programs in our pipeline or the programs that are the furthest along right now. The first would be our Death Receptor 5 program, where we showed some really interesting data we thought in January at a competitor's conference or at the time of a competitor's conference. Then we announced at that point that we're moving into a randomized study with that, with our Death Receptor 5 antibody, IGM-8444, in second line colorectal cancer, which we think is a huge unmet medical need. We're very excited about that, and we're excited about our data that we continue to generate in the single arm study. looking forward to sharing some of those data from the single arm study sometime reasonably soon. The second program that I would like to talk about is, we're taking our T-cell engager, imvotamab, which we think has shown the best-in-class safety profile in non-Hodgkin's lymphoma. We are focusing that on autoimmune diseases with a real new area where we think we can have a leadership position in T-cell engagers for B-cell depletion in autoimmune disease. We've seen some recent, although a small number of patients, some recent very encouraging data using the CD19 CAR-T in severe lupus. We hope that a T-cell engager can accomplish something like the same degree of efficacy, but with much less cost, much more convenience. I think, it's a really interesting opportunity to show that, a T-cell engager CD20 can provide more efficacy than the CD20s that are currently used in autoimmune disease, and hopefully, some of that efficacy that's similar to what you've seen with the CAR T cells in that space. Those are the things we're probably most excited about in the near term. Okay, great. Maybe just for those who are less familiar, with your approach, maybe if you could just briefly talk about how the IgMs are different and potentially better than similar antibodies that are? Right. an IgG background. Yeah. For those of you who may be a ways away from your immunology, I'll remind you that IgM antibody is the evolutionarily the first human antibody to be de-developed, and it's our first line of defense against viruses and bacteria invaders. It's different from the IgG antibody, which is your classic Y shape that has 2 binding domains at the end of the Y. In a simple manner, you can think of an IgM antibody as 5 IgGs arranged around in a circle, and what that gives you is the binding power of 10 binding domains as opposed to 2. I like to say it's the difference between picking up something with 2 fingers and picking up something with 2 hands. It just gives us much more binding power against difficult to bind targets or rare targets. We think it's intrinsically a great format for a couple of purposes. One, we think it's great for cross-linking cell surface receptors for purposes of agonism, and that's what our Death Receptor 5 antibody does. The reason we believe it's much more effective than IgG antibodies is it can cross-link. It can bind multiple Death Receptor 5s on the surface of the cell and send a much stronger commit suicide signal than an IgG can. That was the basis for the Sanofi collaboration that we did last year. Those six targets, three in oncology, three in autoimmune, are all agonist targets. The other thing we think the IgM is really well suited for is to create T-cell engagers, like our imvotamab. You've got the 10 binding domains directed against the target on the cell surface, which gives you the ability to bind low expressing targets and to bind with essentially a 0 off rate. Once it binds, it never lets go. We have 1 binder in the middle of that to the CD3 on the T-cell, which we think that format is what gives us the, what we believe is the best-in-class safety profile in terms of cytokine release syndrome, immune cell, neurologic symptoms, and so forth. Great. you mentioned DR5 and the 8444 program, where you have that, you know, the stronger binding. Mm-hmm. multiple, DR5 receptors. How broadly can you apply that program? Because it's, you know, it's been a tough target and it seems like your approach, you know, could potentially work very well there. Yeah, we certainly think that it will work well. We're very encouraged by the data that we've seen so far. One of the most important things with our program and the format relative-- people have generally, not generally, people have given up on straight IgGs against Death Receptor 5 because the way the biology is, you need to bind three DR5s at the same time in order to send a strong signal, and the IgG can only bind two. You have to rely on some sort of cellular cross-linking or something else to make it efficacious, and it just hasn't worked. People have moved to multivalent approaches to try to bind more DR5s at the same time. The problem that they've had with those is many of them can create something of a polymeric mesh on the surface of a cell. While Death Receptor 5 is mostly on the surface of tumor cells, there also is some DR5 on the surface of normal, healthy hepatocytes, liver cells. Those multivalent approaches that can create a polymeric mesh have had some severe liver toxicity issues, and some of those programs have been halted as a result of liver toxicity, and others have shown significant liver tox. We, to date, have not seen any clinically significant liver tox in any of our patients, and we've now dosed a lot of patients, including patients with liver mets as well as patients in combination with FOLFIRI, for example. We're feeling quite optimistic about our safety profile, which will be critical if you're gonna go after this target. Yep. You've dosed and you've reported data in colorectal patients and you've dosed patients in AML. Do you see a stronger case for solid versus liquid tumors or vice versa, or do you think it's more broadly applicable? I think we hope it's more broadly applicable. Obviously the solid tumor opportunity and unmet medical need dwarfs the liquid tumor need. In AML, those patients are, you know, have very high unmet medical need, but it's a relatively smaller number of patients than colorectal or other solid tumors. I think we're looking forward to our AML data, but the solid tumor focus is probably a much bigger opportunity for us. Great. When you reported your earnings last quarter, you talked about the shift... Mm-hmm. for your other lead asset imvotamab towards autoimmune versus oncology, can you maybe talk about the strategy behind that shift and? Sure. where you see an opportunity to apply this approach in autoimmune? We had good efficacy, we thought, in the oncology setting. I think we reported that in March that we had a 30% complete response rate in DLBCL. As we look at the monotherapy DLBCL market, it just seems really, really crowded and commercially not that interesting. But when we look at our characteristics, we do believe we have the best-in-class safety profile, so we reported a CRS rate of less than 10% with our at 100 milligrams, which we think is easily, you know, best in class. When we look at the opportunities, we know that safety. We have an active molecule. We get complete responses in monotherapy. Doesn't happen unless unless it works well. We think that safety is gonna be critical in autoimmune diseases. We see that as an untapped opportunity, and we hope to be a leader in that space. You've chosen lupus and rheumatoid arthritis, as the two initial indications. Mm-hmm. Maybe how did you come to that decision? I mean, they're kind of both challenging from different ways, right? Yeah. It's been hard to show efficacy in lupus, but then RA, there's a lot of, you know... Competition ...approved treatments. Yeah. And so- Yeah ...more of a commercial challenge there. How did you come to that decision? Well, we see both of these as a great opportunity to establish proof of concept and to establish biomarker proof of concept. We certainly expect that we will deplete autoantibody-producing B cells, and we hope that we get very deep depletion in the spleen and the bone marrow, and the lymph nodes. We hope that that will allow us to start to see the reprogramming of the immune system that you saw with the CD19 CAR-T from Georg Schett and his group. We think that he had success in lupus, so obviously that's a great place to start because you know that in lupus you have an example where you can get efficacy. You look at the other CD20 places where CD20s are used, including rheumatoid arthritis, that's a great place as well to go for proof of concept because you know that CD20 can work there. There's an incredible panoply of autoimmune diseases where you can go with a potential B-cell depleter. Those include places where CD20 has been effective. It includes places where the FcRns have been effective. We have a next-generation T-cell engager, our IGM-2644, which has now just gone into the clinic, which we think could potentially also be used as a T-cell engager in autoimmune disease to hit those B cells that are later on the B-cell lineage. We see it as a broader opportunity than just CD20 by CD3. Yeah. Okay. That makes a lot of sense. You touched on, you know, one of your earlier assets in the pipeline. Wanted to also ask about 7354, the IL-15 by anti-PD-L1. Right. where you've dosed a patient. you know, what do you think are the advantages here of an IGM relative to, you know, all the other, you know, approaches trying to stimulate IL-15? Right. in NK cells? Yeah. Thank you for that question. Our IL-15 is a targeted IL-15. It's targeted to PD-L1, which could be on the surface of tumor cells, or it could be on the surface of antigen-presenting cells. Because of the format, we think the IgM can do a much better job of displaying the IL-15, again, on the J-chain, displaying it to a passing CD8 cell or passing NK cell. Create that cell-to-cell display of IL-15, which is the way that IL-15 is naturally presented from one cell to another. We think that the IgM format can present the IL-15 to a passing cell in a much better way, a more natural way than we can see how an IgG can do it. You had the Kadmon molecule that Sanofi acquired when they bought Kadmon, and it has two binding domains, I believe, to PD-L1, and it has the IL-15 on the FC of that. We think that our format is just a much better cell-to-cell display. Mm-hmm. Most of the IL-15s that are out there right now are not targeted. For example, the ImmunityBio one is not targeted. The Roche IL-15 is not targeted. We had shown some data recently at AACR that indicates, at least in our format, the targeted version works better than the untargeted version. To us, it makes sense. You wanna have delivery as close to natural as you can, so that's delivery from one cell displaying to another cell. Mm-hmm. Great. Well, that session really flew by. Okay. Much going on here and such a interesting platform you guys have and tons of potential. Again, I wanna thank you, Fred, for joining us, and thank you everybody out there for listening. Well, thanks for the opportunity. Really appreciate it. Great. Take care.