iwCLL 2021 | Advances in the use of bispecific antibodies for the treatment of CLL

So, I presented pre-clinical work that we did with a bispecific antibody in my laboratory. And when we talk about, in this context, about bispecific antibodies, what I refer to is antibodies that can recruit T-cells to attack B-cells, malignant B-cells, in my case CLL cells. And so the antibody has been engineered to have a Fc domain and the dual targeting approach with anti-CD3 and anti-CD19. And this has been a molecule generated by my collaborator, Christoph Rader at Scripps.

The key points that we saw with this antibody, well, first of all, it can induce CLL dependent- it can induce T-cell dependent killing of CLL cells and it relies completely on autologous T-cells. So, when we used PBMCs, when we use blood samples from treatment-naïve patients, it actually takes quite a while to mount this response. And we see maximum killing after 7-10 days.

What we were really intrigued by is when we took samples from patients with ongoing treatment with a BTK inhibitor, we saw more rapid killing and more complete killing of the CLL cells. So, it looked like that the patient who were on BTK inhibitor treatment improved the ability of the T-cells to kill the CLL cells. And we saw this was true for both samples from patients on ibrutinib or acalabrutinib. And so the key point here then is that we may not need ITK inhibition, that’s only achieved with ibrutinib, and it’s really, we think it’s really the BTK inhibition that’s required to make this improved efficacy come about.

So, why is treatment with BTK inhibitors improving the T-cell response? So, that’s a question that [inaudible] back in the lab studied, and we studied with several mixing experiments and then also looked at the transcriptome of CLL cells that were treated with ibrutinib, so, from patients who were on active treatment. So, this is really what’s happening in patients being treated. And what we saw is that BTK inhibitors downregulate a transcriptional program that allows CLL cells to inactivate T-cell responses.

So, CLL cells express several molecules that can hamper T-cell responses. And several of these are downregulated by BTK inhibitor therapy. So, this really leads us, first of all, provides a mechanistic explanation for the observation. But it also for clinical application suggests that this could really be a winning strategy of combining bispecific antibody with BTK inhibitors.

So, right now we have- this is a preclinical molecule, so there’s no plan to really bring this to the clinic. But antibodies, bispecific antibodies with similar designs are quite advanced in studies for diffuse large B-cell lymphoma, for some of the more aggressive lymphoma subtypes. These are typically antibodies that target CD20 instead of the CD90 that we use in our preclinical model. So, CD20-CD3 bispecific antibodies, and there’s- I presented some data from epcoritamab. That’s the CD20-CD3 bispecific from Genmab. But similar data has also been presented at the ASH meeting a couple years ago from the genetic antibody mosunetuzumab. And these antibodies are now entering clinical trials for CLL patients. And I think that offers really an exciting opportunity to deepen responses, combine these agents with BTK inhibitors.

And maybe as an important add-on we’ve also seen in our preclinical data that the bispecific antibody was still very efficacious in PBMCs from patients who had started to develop resistance to BTK inhibitors and were progressing on the BTK inhibitor. And I was observed, both in vitro, but then importantly, also in patient-derived xenografts, where we took the samples from these patients who progress on BTK inhibitors, transfer them into NSG mice and treat them with the bispecific antibody. And we saw still very good efficacy against ibrutinib-resistant CLL. So, really an exciting opportunity to bring these novel concepts into the clinic.