Monoclonal Antibodies for Multiple Myeloma

Transcript:Jatin P. Shah, MD: One of the important questions is the mechanism of action, or how these various monoclonal antibodies work, including elotuzumab (or Empliciti). It’s very exciting when you think about elotuzumab. We think of it traditionally like a Rituxan, where it targets the SLAMF7, which is expressed on myeloma cells, and it can target myeloma cells using ADCC (antibody-dependent cellular cytotoxicity) or CDC (complement-dependent cytotoxicity); we need to understand that concept. But importantly, when you think about elotuzumab, you really start stretching immunotherapy because what we see is SLAMF7 expression on NK cells, as well.

NK cells are natural killer cells within the normal part of our immune system. And what happens, you can activate these NK cells—which are normally responsible for killing other infections, tumor cells, funguses, and bacteria—and so they’re a part of your immune system. But what happens here with elotuzumab is you activate the NK cell and, in combination with lenalidomide, for example, use the NK cells to actually directly target and kill those plasma cells. So, not only are you using ADCC and CDC to directly kill the plasma cells, but it acts as a dual mechanism. We’re stimulating the immune system and stimulating the NK cells to actually kill the myeloma cells, as well.

It’s very exciting when you think about the various mechanisms. And they’re all very slightly different between the different monoclonal antibodies. But, importantly with elotuzumab, what you see is not just the ADCC and CDC that we’re used to with drugs like Rituxan, that we as oncologists are comfortable with; we’re also starting to see other mechanisms, including activating the immune system, activating these NK cells, to help kill those myeloma cells, as well.

James R. Berenson, MD: How does daratumumab work? What’s its mechanism of action? These are drugs in a new category of antibody treatment. These antibodies have a multitude of effects directly on the cancer cell—in this case, the myeloma cell—but it turns out they have effects in other cells around the tumor that may be involved in boosting the immune system. And, in fact, daratumumab was originally designed as a way to target the myeloma cell itself, since it bears the protein called CD38. Then it would go to it, and it’d enlist the immune system to kill the myeloma.

We now know it’s much more complicated, in a good way. It actually brings along immune cells that can also help knock off myeloma. So, traditionally, it’s been thought to work through complement-dependent cytotoxicity that’s a well-recognized mechanism through antibodies and an antibody-dependent cell-mediated cytotoxicity. And then a newer mechanism called ADCP (antibody-dependent cellular phagocytosis) involves the monocyte, the phagocyte, which is the cell that that kind of gobbles up things. And that’s a newer mechanism. There are three mechanisms through which the drug is thought to work. But, recently, interestingly, it’s been recognized that the CD38 antibody also gets rid of cells that suppress your immune system. And as a result, T cells, which are a big component of a lot immune-based therapy, now get increased.

It’s interesting that, on the other hand, the CD38 seems to reduce NK cells, which has been the basis of the other recently approved antibody, elotuzumab. So, one could envision perhaps combining these two, which may be a good thing in a way to treat myeloma. But daratumumab basically is another monoclonal antibody that targets the myeloma and says, “Hey, come along immune system and find me.” Then this is hooked on to the myeloma cell, and as a result, you have less myeloma around. But now we know there’s also an additional benefit that it may help boost T-cell responses.

We have two antibodies targeting different proteins. We have the elotuzumab targeting SLAMF7, which is directly on the myeloma cell and, kind of counterintuitively, is also on the NK natural killer cell—but that cell has an activation factor. So, when it binds there, it activates the NK cell, and then when it’s on the myeloma cell, together they dance and the myeloma goes away. Whereas the other antibody, the CD38 antibody daratumumab, really is thought to target the myeloma directly and not have this additional impact. But now we know there may be actually some immune-based effects of that, as well.

Transcript Edited for Clarity

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