iwCLL 2025 | Improving the targeting of surface antigens in CLL: moving beyond monoclonal antibodies

I think that targeting surface antigens in CLL has been a really important feature of how we treat the disease that really adds to other therapies. So I’m sure everyone’s familiar mostly with targeting CD20 with monoclonal antibodies, which in CLL, you know, has efficacy, but is not really resulting in like durable or long-term remissions on its own, but it’s been very effective when added to chemotherapy as chemoimmunotherapy, certainly added to venetoclax and these fixed-duration regimens, adds something to BTK inhibitor-BCL2 combinations, and depending on the BTK inhibitor and the antibody can add to BTK inhibitor monotherapy. So you really see that in most settings, adding an anti-CD20 monoclonal can improve outcomes with kind of other therapies that target more of the disease biology, like our current targeted agents, as long as we’re selective with how we use them. 

I think, though, that’s probably less than we could do targeting surface antigens is how I put it. And I think that there’s a couple ways we could strategically think about targeting surface antigens that might change what we’re able to do with this kind of strategy. I’m not convinced that monoclonals as monotherapy is really going to move the mark on CLL, but in combination regimens, I think we can probably do better than the progress so far. And a few ways to think about this that I’m going to go through in the talk are what targets we use, certainly when we use the antibodies, and how they’re combined with other drugs, and then also something that has been around a while and I think could be used better, which is antibodies that have something kind of with them, so not just monoclonals. You know, bispecific antibodies, which are mostly targeting the malignant cell, like CD19 on a CLL cell, and then CD3 to bring T-cells in, have been widely utilized in lymphomas, have been investigated in CLL, and are still under active investigation. But I think those could be used more. I think antibody-drug conjugates, especially if you have the right payload, could be used more. So I think kind of what we do with these ways of targeting surface antigens will help. I’m not really covering CAR-T or bispecifics because there’s a separate session on immune-based therapies. But I do think that that’s a way to target surface antigens that could be more impactful than just the monoclonal and CLL. 

And then I think there’s actually a variety of targets that could be explored a bit more. I just heard today we’re having a lot of talks on CLL biology and just heard a great talk where they’re talking about ROR1, which of course can be targeted by zilovertamab, which has an antibody-drug conjugate now. We have investigated a monoclonal antibody against the BAFF receptor called ianalumab which was effective added to ibrutinib in reducing residual disease and this was like a Phase Ib study where the drug’s now being developed actually in autoimmune cytopenias rather than CLL. But that was like a dual-targeting antibody with a BAFF receptor, where it targets the surface antigen, but also blocks signaling through the BAFF receptor pathway. So I think that’s a good strategy. My colleague Rajmuth Asami is giving a talk on what could potentially be a new target called Siglec-6. So I think kind of exploring these targets in more detail or thinking about how we might target them better could be really beneficial. And then thinking about how to rationally combine those with other existing therapies, how to time them – mostly we’re giving monoclonals early as an induction. I think now we started to see a lot of exploration as giving them later when disease burden is less. So I think I don’t have a lot of time to cover all these in complete depth, but just thinking about how we could target surface antigens better, thinking through those kinds of strategies.

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