Differentiating Types of BCMA-Targeted Therapies in RRMM


Ola Landgren, MD, PhD:Let’s go from the targets, theBCMA, to the different strategies one could use and the different treatments that are currently in development. These are both cell therapies. There are antibody therapies in development. Can you give us an overview of the different options there are?

Nina Shah, MD:Yeah. Finding this great protein has actually yielded 3 big clusters of treatments that we can potentially develop for myeloma patients. And all these currently are being developed for the relapsed-refractory patients, as it stands now. The first is theBCMA-directed CAR T-cell therapy, or the chimeric antigen receptor T-cell. That’s our cell-therapy bucket as therapies that we have for BCMA.

Then we have the antibody-drug conjugate, which puts a warhead on an antibody that’s directed toward BCMA and allows that to be deployed specifically to the plasma cell. Then you have the bispecific T-cell engagers, commonly known as BiTEs, but really the classic name is bispecific engagers, or infector-cell engagers. This allows for an antibody to be directed both toward theBCMAantigen and, on the other hand, toward the CD3 component of the T cells to bring those 2 together, the effector cells, against theBCMA-displaying plasma cells.

Those are the 3 buckets of therapies that are targetingBCMAthat are currently being developed.

Ola Landgren, MD, PhD:The CAR-T cells, are they cells that come from the same person? You take them out, you reengineer them, you transduce them with vectors, and give them back to the same person. And then you now have this T cell doing the anti-tumor effect. And the bispecifics, they were given almost like a matchmaker.

Nina Shah, MD:Right.

Ola Landgren, MD, PhD:Where you let the cells stay in the patient the whole time but antibodies will bring the T cells next to the myeloma cells.

Nina Shah, MD:Right.

Ola Landgren, MD, PhD:In a way they’re a little similar, but they’re also very different.

Nina Shah, MD:Yes.

Ola Landgren, MD, PhD:And the antibody-drug conjugates, they drag a toxin into the myeloma cell.

Nina Shah, MD:Right, because they don’t require the T-cell section necessarily.

Ola Landgren, MD, PhD:There are no T cells involved there.

Nina Shah, MD:Right.

Ola Landgren, MD, PhD:Talking about these antibody-drug conjugates, what’s the rationale? Could you explain a little more in detail how these antibodies really work, the antibody-drug conjugates.

Nina Shah, MD:Yeah. I think the juice for this particular type of therapy with the antibody-drug conjugates, as I mentioned, allows for a direct targeting delivery of a warhead. In the case of the drug that’s being developed now, which is bela-maf belantamab-mafodotin. That, as a GSK2857916 drug from GlaxoSmithKline plc, has been known to targetBCMAand also on it displays this MMAF toxic substance. That allows that toxic substance to be specifically delivered to plasma cells.

What that allows for is this targeting of killing because that toxic substance interferes with some of the proliferation. As you mentioned, Ola, it’s not requiring necessarily effector cells that come in, although it’s possible because this is an antibody-mediated mechanism that’s been antibody tied to a drug conjugate, that there is some NK [natural killer] cell—mediated ADCC [antibody-dependent cell-mediated cytotoxicity]. Probably most of the work is being done by this toxin.

Ola Landgren, MD, PhD:All these different antibodies that we are starting to use in myeloma, it all started years back, and it was first FDA approved in the end of 2015. The currently approved drugs by the FDA are naked antibodies. So they use antigen derived. So cytotoxicity where they do, they complement derived cytotoxicity, or they have direct tumor kill directly. And now we are dragging in toxins into the cells, and then there are all the other overlaps as well. There’s probably a lot going on, again, that we don’t have the full information about.

Nina Shah, MD:Exactly.

Ola Landgren, MD, PhD:So additional work needs to be done. But the main mechanism of action comes with the drug conjugates is to drag a toxic substance into the cell.

Nina Shah, MD:Right, exactly—to get the business done from killing the cells.

Transcript edited for clarity.

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