What are myeloma targets?

What are myeloma targets? So when we use immune therapies to try to kill cancer cells, like CAR T cells or bispecific T cell engaging antibodies or just antibody therapies, we have to target those immune therapies against a specific molecule. They recognize the antigen or a target on the outside of the cancer cell and deliver some sort of immune treatment directly to that cell, which is partly what makes them so targeted and also partly what makes them effective and different from a lot of the other treatments that we use that are chemotherapy medicines that go into the cell and target the mechanisms of the cell that keep the cell alive and growing. What are some of the target antigens being explored in myeloma? So two of the biggest targets that have been attacked, that are being attacked by our current myeloma therapies are CD38, which is a molecule on the outside of myeloma cells that is latched onto by daratumumab and isotoxumab, two very effective antibody treatments, and then also BCMA or B cell maturation antigen, which is a molecule that's very specifically on the outside of plasma cells and almost no other cells in the body. And BCMA is a target of several therapies, including two approved treatments, the antibody drug conjugate called which carries a chemotherapy medicine directly to the BCMA positive cells, and then also a chimeric antigen receptor or CAR T cell called IDA cell or ABEKMA, which directs immune T cells directly to the cancer cell to destroy them. So there's one other target that's currently being targeted by available therapies. That's called CS1 or SLAM F7. It's the target of elotuzumab, which is also an antibody therapy. And then there are several other targets that are being explored for immune therapies. Probably the two most important ones are molecules that, again, are pretty specific for myeloma cells. One called FCRH5, which is a target of a bispecific T cell engaging antibody called which brings T cells and myeloma cells together by latching onto a molecule on the T cell and a molecule on the myeloma cell, bringing the cells together so that the immune T cell can destroy the myeloma cell. Similarly, another target on the myeloma cell is called GPRC5D, and that's targeted by a bispecific antibody called which does exactly the same thing, aiming the T cell at the myeloma cell just using a different target protein on the outside of the myeloma cell. It's really important to have all of these different targets to go after because we think that one of the mechanisms that the myeloma can use to evade some of these treatments is that it can lose the target from the outside of the cell. And then treatments targeting that protein will no longer work. And so if you have an available other treatment that aims at a different target, that might work just as well whether the patient has progressed on a previous targeted therapy or not, as long as we're aiming them at different targets. And if we end up eventually aiming different treatments all at the same time at different targets, maybe we can even get rid of the myeloma cells completely. Can anti-myeloma combination therapy aimed at different targets be used? The idea of combining targeted therapies makes complete sense. And the only reason we haven't done it yet is because we're so early in this immunotherapy revolution in multiple myeloma. But it absolutely makes sense that if one targeted immune therapy works well and then another immune therapy against a different target also works well, that combining those together might produce even better and perhaps eventually even curative effects as we overcome the different mechanisms of resistance that the myeloma cells can have. What is a target? It specifically pertains to the mechanism of action of a drug. And the target usually is what the drug engages in its attempt to kill the myeloma cell. Now the target could be something on the cell surface and that is commonly the target used for immunotherapies like antibodies or antibody drug conjugates or many of the newer immunotherapies like the bi-specific antibodies and CAR T cells. So these are again antigens that are expressed on the cell surface or the cell membrane. Now similarly there can be targets that are present within the cell and those are usually targets that have a specific function. So it might transmit some of the signals that are needed for the cells to divide or it might be some of the molecules that are responsible for keeping the cells alive. So if when you use that drug which targets one of the small molecules or some of the intermediaries of the cell function, then it can lead to cell death. Now a good example of that could be one of the approved drugs like selenaxor that targets a specific protein that exports what we call a nuclear transport protein and it inhibits its function. We have something called a drug called venetoclax that are going through clinical trial and that specifically targets a protein called BCL2 that is responsible for keeping the cells alive. And by inhibiting the BCL2 you are able to kill the myeloma cells that are highly dependent on that BCL2 function. So the target could mean different things in the context of the specific drug that's being looked at. The ones that are outside are often used for immunotherapies. The ones inside are often the targets for small molecule therapies. The target that is specifically present in the myeloma cell compared to normal cell would make it a better target. So when you talk about targets that are present on the cell surface or the myeloma cell membrane for the immunotherapy approaches, we are looking for targets that are uniquely present on the myeloma cells and not present or present at very low levels on the normal cells so that the treatments can be specifically targeted towards the tumor cells. Now for most of the targets that we have, the ones that tend to be more unique are the ones which are used in the immunotherapy that are present in the cell surface. Many of the other targets that we have within the cell often tend to be involved in normal function as well, but often maybe more, the cell might be more dependent in the setting of the tumor. So the tumor cell may rely more on the target compared to a normal cell and that would also be a good target. So there are a variety of different targets on the outside of the cell, which include some which are already in the clinic like the CD38, which is a target for Dretimumab and Dissertaximab, SLAM-F7 that is the target for Elotosumab, there is the BCMA or the B-cell maturation antigen that is a very favorite target because it is quite uniquely present on or predominantly present on the myeloma cells. That is the target for antibody drug conjugates like Balandamab and also for the CAR-T cells both approved and in development. Now there are also targets within the myeloma cell that are being explored. So for example we talked about Venetoclax which targets the BCL2, there are other inhibitors that are targeting MCL1 which is another member of the same family and responsible for keeping the myeloma cells alive. There are targets that are going after what we call a MIC, which is again a protein that is often responsible for again cell survival in myeloma and the hope is that by going after these molecules which are critical for the cell function and especially targeting more than one at a time and targeting the ones that the tumor is more reliant on, we are able to referentially cause the myeloma tumor cell death and not affect the normal cells. Can myeloma cells lose a target? The myeloma cells can certainly lose a target and it can be an actual loss of the target which could happen for example with the BCMA which is again a good target for a lot of the immunotherapies and some recent studies have shown that there can be a loss of the gene that codes for that protein. So the myeloma cells actually will not express any BCMA so the immunotherapy will not work. Now there can also be a relative change or a relative loss. A myeloma cell that is more dependent on a BCL2 for survival can switch its profile to become more dependent on MCL1 so a drug that targets BCL2 is no longer effective and you may have to use a different drug that targets the molecule that it is more dependent on now. What is NYESO1? NYESO1 is one of a whole group of antigens called cancer testis antigens that are expressed in testis cells and in fetus, fetus cells, fetal cells and probably play a role in early tissue growth and development. They are then largely shut off in the adult, in adult tissues but they find their way to be re-expressed in cancer cells they may be co-opted or used by the cancer cells to bring about growth and proliferation and survival of these cancer cells. They are a relatively special or unique type of cancer marker, cancer antigen to go after because they are relatively selectively expressed on cancer cells and absent on adult tissues and so if they are made to be the target for cellular immunotherapy they will enable the genetically modified or these engineered T cells to be able to go after the cancer and leave the normal surrounding tissues alone. NYESO1 is one of those cancer testis antigens that is expressed in advanced myeloma, refractory myeloma but also on some pediatric cancer such as synovial sarcoma. Is NYESO1 a target on the outside or inside of myeloma cells? So NYESO is an internal antigen that is expressed really only in embryonic cells, very primitive you know fetal cells and also cancer cells including myeloma. They often get re-expressed or turned back on but they tend to be more internal but then the cell will break them into little pieces and express them on the surface.