What are monoclonal antibodies?

What are monoclonal antibodies? So monoclonal antibodies are proteins that are artificially produced. They look almost the same like the antibodies you produce when you have a response to bacteria or to viruses. But the monoclonal antibodies have a special target. They only target the myeloma cell. So the question is how do those monoclonal antibodies recognize the myeloma cells? Well, they really have a little receptor and they bind only to cells that express a certain protein. For instance, it can be CD38 such as daratumumab or ezetoxymab. Or we know that myeloma cells also express SLAMF7. Elutuzumab is binding to SLAMF7. It has a special receptor to bind only to this protein. BCMA is another protein that's expressed by myeloma cells. And we have certain antibodies, for instance, Blenrep, which is a drug-conjugated antibody that binds to BCMA. So the principle of a monoclonal antibody is it has a receptor and it recognizes its target. And we know that the myeloma cell expresses certain proteins on the surface which are the target. And the target can be CD38, it can be BCMA, or it can be SLAMF7. And our monoclonal antibody kind of finds the target with a receptor and after binding to the target destroys the multiple myeloma cells. The naked antibodies such as daratumumab, ezetoxymab or elutuzumab that binds to the target destroys directly the multiple myeloma cells. We know by binding to the myeloma cell, the myeloma cells undergoes apoptosis, which means cell death. But we also know that those cells in this process attract other cells of the immune system. We know for instance that in K cells we call those cells natural killer cells are attracted and when daratumumab binds to the multiple myeloma cells, those natural killer cells for instance are attracted and help to kill the multiple myeloma cells. So it's a combination of a direct killing of the tumor cell or the myeloma cells by the monoclonal antibody and also the attraction of other cells from the immune system and helping to achieve the killing. What are the main side effects associated with monoclonal antibodies? So monoclonal antibodies are usually very well tolerated and in the beginning when we started to give daratumumab which was the first CD38 monoclonal antibody, we were very concerned about because of the infusion related reactions and we gave the daratumumab over seven hours, a very long infusion. We have learned a lot. We know that many many patients, half of the patients have so-called infusion related reaction that occurs mainly with a first infusion, sometimes with a second, with a third, but we know that in all patients with a forced infusion we don't see those infusion related reactions. What happens is that the daratumumab for instance or isotoxymab binds to all the cells that express CD38. Those are the myeloma cells but also cells of your respiratory tract. So that's why you have the feeling when you get the daratumumab for the first time that your nose is runny or that you have a little bit shortness of breath, that you feel some coughing. And what we do in order to manage the side effects, we slow down the infusion, sometimes we stop the infusion. And all of the patients tolerate that drug very very well with a certain infusion so there's not a single patient that had to stop treatment or couldn't receive treatment because of those infusion related reactions. What we also learned is when we give those medications like daratumumab, subcutaneously there is a very slow resorption of the monoclonal antibody into the bloodstream and usually we have less of the infusion related reactions. So what we do is we give a subcutaneous injection of the daratumumab and we watch the patients for four hours to make sure that there is no, I would say, major infusion related reaction requiring oxygen or anything like this but we know that this medication with a slow increase of the concentration is very well tolerated. Are naked antibodies the same thing as monoclonal antibodies? With the recent improvement of monoclonal or the use of monoclonal antibodies, we used the term or started to use the term naked monoclonal antibodies. That means it's just a monoclonal antibody and in contrast to a drug-conjugated antibody, for instance, Blenrep, which has attached a tubulin inhibitor that kills directly multiple myeloma cells. So that's why there is a drug-conjugated antibody and a naked antibody. We don't know exactly which antibody is more potent because we use those antibodies in a different setting. The naked antibodies such as daratumumab and ezatoximab are very often used in combination and upfront when patients are diagnosed, whereas Blenrep, which is a drug-conjugated antibody, is used alone without combination so far and it's approved without combination and it's used in later, I would say, relapses. So it might be interesting to really combine or compare those naked antibodies alone with Blenrep alone and to see which one is more efficient. And another antibody which is not approved for newly diagnosed multiple myeloma patients is elutuzumab. It doesn't target CD38, it targets SLIMF7. So SLIMF7 is again a target and elutuzumab has a receptor for SLIMF7. We also call it a naked antibody. It's approved in combination with IMITS for relapsed multiple myeloma. But again, we have several naked antibodies, only one drug-conjugated antibody, the Blenrep right now. Monoclonal antibodies have really been transformational in myeloma and have improved the lives of our patients to a really huge degree. I'll start by talking about daratumumab, which is an antibody that targets the protein CD38. CD38 is very highly expressed on plasma cells, myeloma cells. It's also pretty highly expressed on natural killer cells, other immune cells. The antibody itself, when it binds CD38, does several things. That target itself has some functions that affect the metabolic state of the cell. Blocking the target alters cell metabolism in some way that is detrimental to myeloma cells. The antibody, when it binds cells, essentially coats myeloma cells, also brings in other immune effector cells, cells like macrophages, for example, which are sort of the garbage man that sort of engulfs other cells. The daratumumab, when it binds, provides an EATNE signal that macrophages listen to and can take up myeloma cells. The other way by which daratumumab may potentially work is that it alters the immune microenvironment. It also depletes or eliminates through other immune cells that may negatively impact the microenvironment or the soil within which myeloma lives, meaning specifically the daratumumab can deplete the cell populations called regulatory T cells and regulatory B cells and regulatory myeloid cells. These are all populations of immune cells within the myeloma microenvironment that promote myeloma growth. So eliminating these cells can further kill off myeloma cells. It allows for an expansion of beneficial immune cells that may help control myeloma as well. Elotuzumab works in similar ways. It actually binds this target called SLAMF7. SLAMF7 is a protein expressed on myeloma cells. It's also expressed on other immune cells such as natural killer cells. So elotuzumab can activate natural killer cells and those cells are felt to be important in myeloma control. By itself, elotuzumab doesn't have clinical efficacy, but when combined with other immune modulating drugs like lenalidomide and also with pomalidomide, that being Revlimid and pomelist, then elotuzumab adds a significant degree of benefit to a combination of elotuzumab Revlimid and dexamethasone or elotuzumab and pomalidomide and dexamethasone, potentially through a natural killer cell mediated mechanism. These combinations of antibody with immune modulatory drug are now approved for both elotuzumab with Revlimid or pomelist as well as daratumab with Revlimid and pomelist. Since the filming of this segment, ezatuxumab or sarclisa is another monoclonal antibody that has been approved in myeloma. Monoclonal antibodies are engineered antibodies that are designed to attack something specific on cancer. Our body makes antibodies all day long to fight the flu, to fight COVID, to fight anything. But we know that all the cells in the body have different markers that stick up on them and we call them all CDs. CD1, CD2, CD3. And CD stands for cluster of differentiation. How do you tell one cell apart from another? All B lymphocytes have CD20 and all myeloma cells have CD38. Retuxin is an anti-CD20 antibody. It finds any cell that has CD20 sticking up, latches onto it and attacks it and tries to kill. So they're basically as if our immune system got really, really smart in a lab and instead of just attacking the flu, we get it to attack a marker that's specifically on cancer. Why do people relapse on CD38 monoclonal antibodies? This membrane protein gets shed. You lose the expression. Then you don't have anything to respond to. If you don't have the target that you are giving treatment against, then you will lose the effect. And that's one explanation. The most reasonable explanation is the cytogenetic. The more aggressive disease, the more ways that the cancer cells will find to resist the treatment. But one of the mechanical explanations that the cells lose the expression and we can see that. And you can treat with the Dertrum. If you have a patient on very nice response several months, several years and they get progress, you can treat them with something else. And in need, you can retry the Dertrum if you have done that and you will get response again because the cells will increase their expression of the CD38 after a while from stopping it.