SOHO 2026 | The rationale for BTK degraders and their emerging role in resistant CLL

So BTK degraders, I think, are a really important class of drug. So BTK degraders, if anyone’s not familiar with them, bind the BTK protein, even just briefly, and cause it to be destroyed by the cell’s own protein destruction machinery. And there’s a couple of ways that’s done. A common one is ubiquitination, but really what they do is they tell the cell to eliminate BTK, so the protein’s gone, so if you do Western blots to look at BTK protein, if it’s present in CLL cells that have been treated with the BTK degrader, it’s not there, and that really just removes it. There are two major benefits to this: one is that it overcomes these resistance mutations to a large extent, because even the brief binding of this in the presence of resistance mutations, most of them, sorry, mutations that confer resistance to the pharmacologic BTK inhibitors, not the degraders, can cause the protein to be removed and reestablish effectiveness. So it still blocks B-cell receptor signaling because the protein’s gone. There are a few mutations that confer resistance to degraders, so it’s not perfect, but you see a wide variety of BTK mutations that mean that our pharmacologic inhibitors don’t work well. If you have a degrader and it removes the protein, you know, the CLL gets better. I think the other major rationale for this is that BTK as a protein has more than one function. Most of the time we talk about the function where it causes signaling through BTK, then PLC gamma 2, and downstream. But it has a scaffolding function, which isn’t actually the enzyme function of the protein. It’s just the fact that it’s there and other proteins can kind of bind or hang on to it. And that has some ability to kind of establish B cell receptor signaling or drive the CLL. So removing it removes not only the enzyme function of it, which is mostly what we talk about, but also removes the scaffolding function of it or its presence there. And so that’s kind of the other major reason that degraders are effective. I think the data we’ve seen so far with them is remarkable. This is going to be huge for patients and already is huge for patients, especially those who have gotten in trials, in resistance to covalent or non-covalent BTK inhibitors. So in pharmacologic BTK inhibitions not working, degraders are definitely a good option. I think it’s also a potentially very effective strategy maybe in combination for fixed duration therapies. We haven’t seen a lot of that yet, but I think that’s a strategy that certainly should be tried, and I look forward to learning what else they’re useful for.

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