Shattuck Labs, Inc. Common Stock Wells Fargo 21st Annual Healthcare Conference

Sure. Shattuck is these days entirely focused on blocking DR3, which is the sole receptor for TL1A. This is a very simple axis where you have a single ligand TL1A binding to a single receptor, DR3. We will get into this in a lot of detail, I know, but right now we are the sole company that is focused on blocking DR3. That comes with pretty significant advantages versus blocking TL1A related to immunogenicity and also target stability.

Sure. The relative potential durability of axis blockade assertion relates to the fact that DR3 and TL1A have very different biology as proteins. DR3 is primarily expressed by circulating lymphocytes and also endothelial cells, and when a cell has undergone a fate decision where it has decided to turn on DR3, that cell never turns DR3 off again. It represents a stable target. TL1A, on the other hand, is not constitutively expressed. It is expressed by tissue-resident antigen-presenting cells, but only when those cells have been exposed to immune complexes or different toll-like receptor stimuli. When that happens, TL1A gets turned on and off in very short pulses. The implication of that is that when you are trying to block TL1A, you are chasing a moving target. When you are trying to block DR3, you are not.

Let's talk about the aspects of our existing data that might speak to this. When folks who have developed TL1A-blocking antibodies are trying to derive a pharmacodynamic marker that might help inform their dose, the way that they have gone about this is by measuring the magnitude by which the circulating concentration of TL1A goes up after treatment with an antibody. You can think about whether that is a good or a bad thing, but that is sort of separate from the logic I am walking through here. You are measuring whether you reach a maximal plateau in the amount of TL1A that is in circulation, right? That is not telling you what is happening within the tissue, and it is also not telling you whether the antibody is actually occupying all available TL1A.

When you are measuring whether we have achieved blockade of DR3, the way that we are doing that is using a TL1A binding assay. We are collecting samples from the subjects that are treated with our antibody, and we are measuring whether there is any ability of TL1A to bind a DR3-expressing cell. It is an assay that is much more directly speaking to the pharmacodynamics of the axis and is telling us not just that all cells are occupied with our antibody- but there is no ability of TL1A to bind cells that have been bound by our antibody.

Yeah. There's a couple of layers to why this might be the case.

Yeah. Number one, until relatively recently with the tulisokibart positive data in ulcerative colitis, all we had for the axis was a failed trial of duvakitug in asthma.

Right? There wasn't proof of concept for the axis until fairly recently. The other variable here is that when you're trying to build a TL1A-blocking antibody, all that antibody has to do is provide steric hindrance for the ligand blocking to the receptor, because TL1A itself doesn't signal.

Right. When you're trying to build a DR3-blocking antibody, you have to have an antibody that binds an epitope which interferes with TL1A binding and that doesn't cause what's known as residual agonism for DR3.

Okay. That is a significant challenge in picking a good antibody.