Another Way to Leverage NK Cells to Kill B Cells, This Time Without CARs Save

Hey there everyone. My name is Al Kim. I'm one of the leads for cellular therapies and cellular approaches to treat autoimmune diseases. And I'm reporting from EULAR 2026 in both rainy and sunny London, UK. And we have a series of topics that we're going to be able to present over the next few days related to abstracts that are being presented at EULAR. And the first one I want to talk about today is actually going to be four different abstracts but all related to the exact same product which is actually a natural killer cell product and I'll get more into the details of that. So the title of this presentation is going to be another way to leverage NK cells to kill B cells, this time without CARs.

So what's the background behind the story? You may remember in our immune system we have two cells that are cytotoxic, i.e. they can directly kill another cell. One of our T-cells, specifically CD8-positive T-cells — these are leveraged in CAR T cells quite successfully in certain diseases — and then the other one are NK cells, or natural killer cells. These have been used as CAR NK cells, but in this particular set of abstracts there are data here that leverages a unique natural killer cell that does not have a CAR, and it's used to deplete B cells. So welcome to AB-101, which is the name of this particular product, which is a combination of NK cell therapy plus rituximab in both difficult-to-treat RA, scleroderma, and Sjögren's disease.

So the specific abstracts that we'll be covering are going to be poster 1177, which is presented by Dr. Mo Venezuela, latebreaker abstract number three, and oral presentation 129, both of them presented by Dr. Norman Galais, and then poster 0355 by Dr. Geratz.

So the reason why there are multiple abstracts I'll get to in a second. But let me first talk about what AB-101 is, because this is a pretty ingenious way, if not a little complicated, to be able to leverage the NK cell to kill B cells. So AB-101 is a non-genetically modified — i.e. it does not have a CAR construct. So it's not a CAR NK, it's just an NK cell that is allogeneic. It comes from a healthy donor that's given to a different recipient, right? It's a natural killer cell therapy that's derived from cord blood units. What's unique though about this type of cell is that it has a polymorphism in its Fc receptor, specifically at amino acid 158, that confers enhanced affinity to the Fc portion of IgG.

Now you may have thought, well, I think I've heard about this before. The type II monoclonal antibodies like obinutuzumab — those are antibodies where there is a fucose missing, i.e. they're afucosylated IgGs, that also then confers enhanced binding to Fc receptors on natural killer cells. So instead of modifying the antibody, i.e. type II monoclonals, we are looking at the same goal but from the opposite lens, i.e. what you're doing is using a specific type of Fc receptor that has high affinity on the NK cell. So here what you're able to do is use traditional B-cell-killing monoclonal antibodies such as rituximab instead of obinutuzumab in order to enhance killing.

So the outpatient treatment regimen is complicated though, and I think this is something that we need to talk about going forward. First of all, they get lymphodepleting chemotherapy — both fludarabine and cyclophosphamide — immediately chased by rituximab, and then after that they get three weekly doses of this NK cell, the AB-101. It's 1 billion cells given at day three, day 13, and day 20. So it's a pretty complicated process, but one of the interesting advantages of this particular regimen is that it can be done all as an outpatient, right? And so you don't need to hospitalize patients for this.

So let's focus on the RA LB3 abstract that was presented by Dr. Galais. In this particular abstract what they were able to report is six participants with difficult-to-treat rheumatoid arthritis. All of them were able to continue their conventional background therapy, which is going to be a standard DMARD. And what they showed were a couple of things. First, safety-wise, there was no cytokine release syndrome, no ICANS, no hypogammaglobulinemia, graft-versus-host disease, or any serious adverse events. This is exactly what you want if you want a pure outpatient regimen, right? Nothing that's going to make you concerned where you have to give something like tocilizumab and hospitalize them. There were a few adverse events related to the treatment: six nausea, four headache, three UTI, two diarrhea, two vomiting — all of them grade one or two. So they weren't very significant.

The B cells that were detected by a highly sensitive assay were completely gone in these patients by day 28, and then B cell reconstitution was observed about 6 to 12 months later. So what's interesting is when you look at the
therapies that they were on, three out of four were able to discontinue their background therapy, and then three out of three were able to stop glucocorticoids, but only four out of six were able to achieve moderate disease activity from high disease activity, and that was the best they got. So most patients got better but they didn't go into remission, and they certainly didn't even go into low disease activity. So efficacy is a bit of concern with this. They also report in other abstracts at EULAR a good response in a single Sjögren's disease patient and a single scleroderma patient. So this is something that may be disease dependent — we've talked about in prior discussions, especially at ACR, where maybe targeting BCMA may be important here for RA versus CD19 and other autoimmune diseases.

So this abstract is interesting because it's a complicated regimen, but can be done purely as an outpatient. The safety confirms that, at least based on these small ends, and it looks like the issue here, at least with the RA, is going to be the efficacy, and again this may be a target issue.

So this opens up a few questions, right? First of all, wouldn't the lymphodepleting chemotherapy, or LDC, deplete the B cells themselves? Right, this is chemo. And you're right, the answer is correct. But it only does it in the periphery — i.e., the blood and lymph node B cells. Tissue-based B cells aren't touched by lymphodepleting chemotherapy. So this is the reason why the NK cell is needed.

And then the second issue is, okay, we talked about how complicated this regimen is — why not just use obinutuzumab, right? Isn't this just obinutuzumab except you're taking advantage of a high-affinity Fc receptor on the natural killer cell? Well, you may not get as much cytotoxicity, possibly due to the fact that you're not having enough NK cells. A billion NK cells were injected three times over a 3-week period. So if you wanted to say, you know, I think I can make this work with an obinutuzumab approach — you know, I can mobilize these cytotoxic NK cells from the bone marrow using an IL-15 super agonist, it's actually called N-803 — one has to wonder whether this approach could be used and be able to completely avoid the need for lymphodepleting chemotherapy, because you get the injection of obinutuzumab, you get the injection of the IL-15 super agonist, and now you have all of these NK cells coming out that are going to act on the obinutuzumab. Maybe, maybe not.

And then the other thing you might be thinking is, why not just combine AB-101 with a type 2 monoclonal antibody with obinutuzumab? This might enhance efficacy, but as we've seen with the CAR NK cells and T-cell engagers and CAR T-cells, when you have a more cytotoxic or better killing product, you may have higher rates of cytokine release syndrome and other related toxicities that render this approach impossible to do completely as an outpatient. All right, so that is something to consider.

So regardless, this is a really interesting approach, and the innovation that we're seeing in this field to be able to enhance B cell depletion approaches beyond what is currently available is notable. Thanks.