What are bispecific antibodies? Bispecific antibodies are a group of drugs which have two hooks, so as to speak. One attacks the cancer cell, attaching to an antigen that it is primed to recognize, and the other is attaching to the immune cell, the T cell, bringing the T cell in the proximity of the immune cell and thereby increasing its ability to kill the cancer cell. These are drug classes that have been shown to be effective in certain cancers and commercialized already in, say, acute lymphoblastic leukemia. In myeloma, there are several of these in development, and they're all showing very promising initial results. I think that the bispecific antibody is a generic name for a drug class. Several of these have been given specific patented brand names by various pharmaceutical companies. For example, a bite is a bispecific antibody that is made by Amgen. And likewise, there are others that have acronyms that have been patented by certain pharmaceutical manufacturers. Bispecific is the example I give to my patients with bispecific antibodies. think of a fork that has prongs on both ends, and each end, the prong sticks into something. The bispecifics, most of the ones out there, with one exception that's actually very interesting, are all sticking the fork into the BCMA, which is the same target as belantomab, and the same target as most of the CAR T cells right now. One side of the fork is sticking into the BCMA target on the myeloma cell. The other end of the fork is stuck into one of your immune cells. So it's a twofold, or bispecific, in that it's sticking two different cells. One of them works directly, the other one brings the other cell in the close proximity, so you get double whammy by having the fork. So the fork probably bends, if you will, or the fork's not very big, the interim between, because you've got the one sticking in one, the other one sticking the other, and they get close together, and the one that's sticking the BCMA can work independently, but you also have the advantage of the immune cell being brought into the close proximity to the myeloma cell, so you get a double effort for the same drug. Most of the bispecifics right now, there's like six of them that are the furthest along. Five of those six all use BCMA. The sixth one uses a different target for the sticking in the myeloma cell part of the fork, which means you could probably get one bispecific and then get the other bispecific in the future, because they don't have the same target. I think most patients by now know about, for example, daratumumab, or isotuximab, or lutetumab. Those are monoclonal antibodies. They have one target that is on the cancer cell, and they bind to the target, and the immune system gets activated by some natural mechanism, usually through complement, but they're not binding to anything else. The bispecific antibodies, their goal is to bring together some cells in the immune system at killing other cells and put them in close contact with the myeloma cell. The vast majority of the bispecific antibodies that we have in development, they are anti-BCMA, which is a protein present on the surface of the myeloma cells, and they have an other arm that grabs CD3, which is present on our T cells. T cells are one type of lymphocyte. It is the most abundant type of lymphocyte in the blood, and the T cells, they are specialized in doing direct cell-to-cell kill. When you bring together those T cells that kill other cells with the myeloma cells, those T cells get activated, and they attack the myeloma cell. That is one way to engage the T cells. That's why they're calling T cell engagers. But regardless of what they were initially trained to do, to now be redirected and attack the myeloma cells. In a way, it kind of resembles what we do with CAR T, which is also you remove the T cells, insert a gene on that T cell that reteaches that cell to kill the cancer cell, but now you don't have all the delay and the complexity of harvesting cells, manipulating cells, and infusing back. So it can be a much faster therapy to deliver. There are several bi-specifics in development. Most target BCMA, but I think very important, there are other targets that are being approached with the same level of efficacy. For example, GPRC5D, we're going to hear that more and more often, and FCRH5. What is their mechanism of action? So the mechanism of action of a bi-specific is mainly immune-based. This is something that relies on the body's immune system to eradicate the cancer in contrast to antibody drug conjugates, which rely more so on the chemotherapy payload that is responsible for cell kill. Do bi-specific antibodies attach to a specific type of T cell? T cells in particular are very important as far as fighting cancer. There are different types of T cells. I think with regards to the new therapeutics in the myeloma space, specifically the bi-specific antibodies, those are really directed to engage what we call a cytotoxic T cell. These are effector T cells which are basically designed to identify and kill cancer cells or infection. So what a bi-specific antibody does, on the one hand, it attaches to the surface of the myeloma cell through a specific marker sitting on the surface of the myeloma cell, and then on the other hand, it binds to something called CD3 on the surface of the cytotoxic T cell. This creates what we call in the business an immune synapse, and what that means is that there's a signal that's sent through this bi-specific antibody into that cytotoxic T cell, which basically tells it to activate. It releases all of these evil humors onto the myeloma cell and thereby killing it basically. So we're seeing a lot of therapies that rely on the T cells, CAR T cell therapies and bi-specific T cell therapies. And a very justifiable concern exists that as patients go through multiple therapies for myeloma, those T cells get quote unquote exhausted. That means they are not able to engage so well or release the products that are necessary to kill the myeloma cells so well. So there is a concern. That being said, the efficacy of those agents is still very high in this population. We're exploring and looking forward to ways to revigorate those T cells. There's nothing really proven and there's also no test that tells us, okay, your T cells are not good enough, you shouldn't get this therapy. I think it speaks for the strength of those treatments that even patients who have been heavily pretreated seem to benefit. However, there's hope that as we move those therapies to earlier lines and patients have better T cells, we're going to have even better and more durable efficacy. So we don't have data on that specific question, whether if you've had T cell exhaustion, whether that means that these will not work. T cell exhaustion is just that your immune system just keeps beating up, beating up, beating up, beating up. And it's sort of like as you get older, your knees get creaky and you may or may not need have a knee replacement or something like that. But if you don't have a knee replacement, you know, they creak and you've got osteoarthritis of your knees, the T cells may get old and cranky. And certainly when you have bad knees and you have no cartilage left, it's harder to walk up the steps. But that doesn't mean you can't walk up the steps at all. So it's possible that you can get some effect based on T cell exhaustion theory, but that doesn't mean it's going to be an all or none effect. Now that needs to be studied. We do not have the answers to that right now. How are bispecific antibodies administered? So all the antibodies currently are either IV or subcutaneous injections. It just varies on the different antibody, but some of them are IV, some of them are subcutaneous, some of them are given weekly, some of them are given every two weeks. There's none of them right now. I believe they're given less less frequently than every two weeks. So somebody's going like, well, what about Darzalex? Can you give it every four weeks? And the answer is the bispecifics right now, not the trials did not use in every four week schedule. They are doing studies to see if they if the effect lasts that long. But the first ones that get approved are going to be utilized in a more frequent dosing schedule. So the bispecific antibodies, I think without any exception, they were all were developed initially for IV administration. The schedule of administration changes. Most of them start with a weekly administration. Some of them have a process where you go to every other week or even monthly or every three weeks depends on the agent. However, what most of them have found out is that if you take the same drug and administer subcutaneously, you can actually have less toxicity and you can easily get to the intended dose. Are bispecific antibodies being used as a monotherapy or in combination with other anti myeloma therapies? Currently, most of the bispecifics are being evaluated as monotherapies, but it's only a matter of time before they start presenting the results with combinations. They are already being designed and trials are ongoing in combinations. But the first approvals, which is going to be as a monotherapy for those agents. What side effects are being seen with bispecific antibodies? The great news for patients is those therapies are being developed very rapidly. They're shown to be safe past the first week when you can have a little bit of problems with CRS, but that's usually you're in close watching. Beyond that point is really is tend to be a smooth sailing and they're greatly, greatly expand the row of opportunities for patients as we identify several different targets. The main toxicity of those bispecific antibodies tend to be cytokine release syndrome that we probably heard about before in CAR T cells. So that's a reaction where patients can have fever. If it gets worse, dropping blood pressure, breathing problem, and in very advanced situations like organ failure. And those are rare. I mean, having some CRS is common, but having severe is rare with bispecific. And almost always is happening on the first or the second dose. So what most of those bispecific have found out is you can greatly mitigate that by administering what we call step up dose. So you give a tiny dose, two, three days later you get a intermediate dose, two, three days later you give the intended dose. And by doing that, you quickly get patients to the dose that you think is going to be And you drop that CRS to nothing or grade one, grade two, which is most patients just a fever. So that and that is being administered subcutaneously, which has been proven to have less toxicity. So it's really amazing to see how fast this went from early therapy with a lot of concerns and no efficacy to something that is being quickly fine tuned to become a very effective and safe and in many ways very practical therapy for patients. Because for bispecifics you can have the cytokine released in them with the first few doses. In most cases, or I think of maybe all the cases, all the ones that are being developed, you get the first few doses in the hospital. But once you pass the first two or three doses, the risk of CRS is essentially zero. So that are amenable to clinical administration. So I have patients come to the clinic, they see the doctor, get the blood work, get a subcutaneous shot and go home. I think as like with everything else, as we all become more familiar and more comfortable with those therapies as they hit clinical practice, I foresee a time when patients will get even the first couple doses entirely in the outpatient setting. But for now on, patients usually stay in the hospital for about a month, sorry, for about a week, mostly to be observed and have interventions if they develop some CRS.