What targets are being explored in myeloma therapy?

What targets are being explored in antibody therapy? That's a great question. Actually, I think along with the targets, there's also a lot of antibody-based immunotherapies that have either been approved or are in clinical trials. Just to take two steps back, I would explain even when we say antibody, that's a fairly generic term, and then there's kind of multiple different ways an antibody can be used as a treatment in the drug development scheme, along with multiple different targets that could be used. How are antibodies being used in myeloma therapy? If we just go back to about 2015, when the first monoclonal antibodies were approved for multiple myeloma, they were daratumumab and elotuzumab. They are what we call naked antibodies, meaning that they're basically monoclonal. They all look the same, and they help activate your immune system. That immune system cells that help are mostly what are called the natural killer cells and the macrophages. As time went on, I think, and different therapeutic approaches were tried, the next class of drugs that were approved are what we call ADCs for short, stands for antibody drug conjugates. In these cases, you actually take the antibody and you add what's called a payload. A payload is usually a chemotherapy that basically gets delivered selectively into myeloma cells and destroys the myeloma cells. Now, fast forward to 2022. A lot of the excitement are over what we call bispecific antibodies. These are very similar to the initial monoclonal antibodies, except instead of having the two hands that see the same door. In this case, one of the hands actually sees the myeloma cell and the other hand actually sees the immune T cell. That's how these antibodies work. How do they actually detect or identify what is a myeloma cell or what is a T cell? That's exactly where we get to your question about the different targets. Going back, elotuzumab, for example, the target for that is called SLAMF7 or CS1. For daratumumab, it's CD38. Shortly after daratumumab was approved and developed, there were a number of other antibodies that recognized the same target. They're not exactly the same drug because they recognize a different part of that CD38 target, but closely after it was isataxima, which has since actually also received FDA approval for relapsed refractory myeloma in combination with either pomalidomide or Kyprolis. There have been actually one or two other ones also that are really further down the line in being able to be available for patients. At least the one approved antibody drug conjugate we have, it is BCMA. I think a lot of people are used to hearing the term BCMA because that's also a target that's not only used for antibody drug conjugate, but also was used as the main target with the first trial in myeloma, CAR-T trial in myeloma, using BCMA. Now a lot of most of the bispecific antibodies use the BCMA target to find the myeloma cell. Now speaking of the bispecific antibodies, like I said, there's actually like two different hands. One can recognize BCMA that's found on the cell surface of myeloma cells, and the other actually identifies a marker or a protein called CD3. Those are found on the surface of the T cells this time. So basically by shaking hands with the myeloma cell and the T cell, the T cell gets activated and does its job in destroying the myeloma cell. In addition to BCMA, other targets are being explored for bispecific antibodies. Two of these newer targets are FCRH5, which is the target for the bispecific T cell engager named Sevastomab, and GPRC5D, which is a target of Talquitimab, another bispecific antibody that currently is in clinical development. What is GPRC5D? I would say the most popular target for CAR-Ts and bispecific antibodies has been historically BCMA or B cell maturation engager, but there's been other targets being evaluated as well, and one is called GPRC5D, G-couple protein receptor 5D is the long term for it, but we just call it GPRC5D. So it's also highly expressed on plasma cells, relatively specifically to the myeloma cells, although there is one other target that they have found where GPRC5D is expressed, which is on the hair follicle actually. And so these GPRC5D targeted therapies, bispecific antibodies like Talquitimab have shown to be very effective in myeloma, similar to Toclostomab, but they are seeing some side effects, primarily palmar plantar skin changes, basically areas, basically rash on the skin of the feet and the hands, also some nail changes as well that is being observed with some of the Talquitimab studies, and so this is likely an on target effect of the GPRC5D affecting some of the areas of the skin. Why is CD38 chosen as a target? It's a protein that is expressed entirely in the myeloma cells. I mean, that's natural to target. It's also a protein in the membrane of the cells that is mostly expressed in the myeloma cells and the B cells, but you have it in your lungs, you have it in your intestine, that's why some people get respiratory tract symptoms on the first treatment, and that's why some of the patients get the areas and so on. You have it on your anchors cells, you have it on the platelets origin cells, you have it on the atheroblasts, so it's expressed not everywhere, but in several places in the body, but mostly in the myeloma cells. The expression of CD38 in myeloma cells, it's between 92 to 95% of all patients, but all patients don't express CD38 on their myeloma cells. CD38 actually can be found in other cells, including B cells. It is actually even found in red blood cells, which is why for those who may have been on it already, they've had to go special testing before starting it with the blood bank, because it can interfere with the cross-matching. It is a great way of identifying plasma cells, but alone you have to use it with other markers, for example, to isolate a plasma cell or a myeloma cell. Just that if you have myeloma, you have a lot of these abnormal plasma cells, and most of what it does is destroy the abnormal plasma cells or the myeloma cells. SLAMF7 works maybe a little differently. I think we still don't know exactly how it works. It is a target that's uniquely found on the myeloma cells or the plasma cells, but interestingly enough, it's also found on T cells and even what's called T regulatory cells. One of the ways we think it works is not only does it activate your own innate natural killer cells to find the myeloma and destroy it, but we also think that it activates directly by binding some of these T cells to make a shift between the T cells that are pro and against immune activation. That plays a second role in the way we think elotuzumab works. What does BCMA stand for? It stands for B cell maturation antigen. For the most part, it's on B cells and plasma cells, and it actually is involved in the natural growth of the B cell from precursor. We know that there's specific what we call ligands or natural proteins in the blood that actually are, as part of normal physiology, are supposed to bind in and activate the T cells through maturation. What is FcrH5? FcrH5 is another new target that's being evaluated in multiple myeloma. We probably have the most data with this drug called savastimab, which is being developed by Genentech. It's a bispecific antibody that targets a T cell and FcrH5 on the myeloma cell. This data, early data, has been reported at several congresses or meetings in myeloma. The early data looks very promising, very similar over response rates to bispecific antibodies targeting BCMA and GPRC5D. It's nearly exclusively expressed also on plasma cells as well, so it looks like to be a very promising target with low or little off-target effects.