(Guest Lecture): April 2024 - The Emerging World of Bispecific Antibodies

My name is David Cothey. I'm a physician at Sylvester Comprehensive Cancer Center at the University of Miami. My focus is in caring for patients with multiple myeloma. I'm also a researcher and I focus on studying the immune system and how we can better utilize immunotherapy to fight the disease. Today I'm going to be talking about the emerging role of bispecific antibodies in the treatment of multiple myeloma. During this presentation I will be talking about the important role the immune system has in multiple myeloma. I will explain the mechanism of action of bispecific antibodies. I will review the indications and the dosing that the FDA has approved for bispecific antibodies. I will outline some of the adverse effects that patients may experience during therapy, how we treat those adverse effects, and importantly how we can prevent those adverse effects. I will then review the efficacy from the clinical trials of bispecific antibody. I will finish with some mechanism of resistance that you should be aware of. And finally I will touch on some of the up and coming bispecific antibodies that are not yet approved. Since I'm the first talk I thought I would give a brief introduction to multiple myeloma, although I know many of you in this room already know about the disease. Multiple myeloma is a cancer of plasma cells. Plasma cells are a type of immune cell commonly found in the bone marrow and they normally secrete immunoglobulins, also known as antibodies. These are proteins that bind to viruses, bacteria, and they are cleared by the immune system. When plasma cells experience damage to their DNA they become tumors. When they start growing rapidly and causing harm to the body they become cancer cells. The proteins that continuously are excreted by those plasma cells that are myeloma cells are known as monoclonal proteins. Mono for single, clonal for copy. And they can be detectable in the blood and the urine and it becomes an important test for you and your doctor in monitoring the disease. These plasma cells that become myeloma cells inside of the bone marrow influence the bone marrow cells so that the bone marrow starts to degrade, lesions start to form in the bones, fractures can occur, calcium can be leached into the blood known as hypercalcemia that may require hospitalization. These monoclonal proteins can stick to the kidneys, clog them, and cause kidney failure. And finally the myeloma cells might overcrowd the bone marrow causing reduction in normal blood cells such as red blood cells, we call this anemia. This cancer represents 1% of all cancers in the United States or 10% of blood cancers. It's the second most common hematologic malignancy. There are 32,000 new diagnoses made per year in our country and 13,000 people die from the disease in our country per year. For reasons we are trying to understand, it's more common in men and in African Americans. The median age of diagnosis is 65 right at retirement age and the overall survival is six years but many patients are living well beyond this benchmark. Plasma cells are a cell type within the immune system. The immune system is complex. The immune system is composed of multiple different cell types. You may think of it like a family tree where the parent at the top is the hematopoietic stem cell. There are two major branches called the myeloid branch and the lymphoid branch. Within the lymphoid branch you have T cells, B cells, natural killer cells, and plasma cells are a subtype of the B cell. I'm going to be talking a lot today about T cells which is a sibling you might think of of B cells which are really important in fighting cancer and other diseases. The myeloid cells include cells like neutrophils which you may have heard about when you get blood tests, also very important cells in fighting infection. And there are multiple organs throughout the body that the immune system travels through. These are the lymph nodes, the lymphatic vessels, the spleen, the thymus which is where immune cells undergo maturation, and of course the bone marrow which is where it all begins, where all the cells are made and distributed throughout the blood system. I mentioned that the T cells are an important player in the immune system especially for fighting cancer. So when a myeloma cell has damage to its DNA, the protein that results from that damage gets displayed on its surface. T cells then recognize that something is wrong with that cell. They then bind to it and elicit an immune response by sending protein signals that cause that tumor cell to die. This is a very important mechanism that helps prevent cancer in healthy people all the time. In fact, people probably have cancer from childhood and our immune system is finding those and eliminating those so they never become a problem. However constant overstimulation of the immune system can lead to exhaustion. When exhaustion occurs, the immune system no longer recognizes and kills the cancer cells as it should. As a result, the cancer begins to proliferate and grow out of control. So the purpose of immunotherapies are to help boost the immune system. The immune system is no longer capable of eliminating the cancer itself. Clever scientists have identified ways to help redirect and boost the immune system to fight cancer. We have four approved classes of immune therapies for the treatment of multiple myeloma. They are the immunomodulatory drugs, the monoclonal antibodies, the bispecific antibodies, and the chimeric antigen receptor T cells. The immunomodulatory drugs include linolitamide, pomolitamide, thalidomide. These are oral medications that stimulate T cells, natural killer cells to fight the cancer. They also inhibit inhibitory cells like regulatory T cells that would normally stop the immune system from fighting the cancer. More recently, monoclonal antibodies were developed. These include elotuzumab, daratumumab, ezotuxumab. These are antibodies that bind to proteins on the surface of myeloma. These are called CS1 and CD38. Binding to these proteins on the surface of myeloma elicits an immune response directed at the cancer cells. The next immunotherapy to be approved for chimeric antigen receptor CAR T cells are CAR T cells. These are genetically modified T cells from the patient's body. The cells are removed, sent to a lab, modified to have a receptor to recognize tumor antigens, in this case BCMA, B cell maturation antigen. When they're infused back in the patient's body, they find to target and kill cancer cells expressing that protein. Dr. Green will be speaking a lot about CAR T cells after my talk today. What I'm going to be focusing on are the bispecific antibodies. Bispecific antibodies are immunotherapy that direct T cells to myeloma cells. Here's a cartoon that shows what a bispecific antibody looks like. It's a linker protein. It links together two cells. On the purple end here, you can see that the linker is binding to BCMA, or B cell maturation antigen. BCMA is a protein, and it's almost exclusively found on plasma cells and myeloma cells. So it's not found on healthy tissue, like lung tissue or liver tissue. It's specific to these two cell types. It also binds to CD3 on the other end. That's the blue part of the molecule. CD3 is only found on T cells. So by binding T cells on one end and myeloma cells on the other end, it links them together. That linkage causes an immune response directing the T cell activity at the myeloma, and hopefully killing that cell. In the United States, there are three FDA approved therapies for multiple myeloma. These are teclistumab, alrinatumab, and talcuitumab. I've shown here the brand name and the manufacturer for your interest. So teclistumab and alrinatumab bind to B cell maturation antigen, whereas talcuitumab has a unique target binding to the G protein coupled receptor class V member D, or GPRC5D. Just suffice it to say that these two targets are exclusive to myeloma cells, and having different targets is beneficial in the event that one of the targets is no longer expressed on the myeloma cell. They were very recently approved in 2022 and in 2023. So when a drug undergoes study and development, its data is presented to the United States Food and Drug Administration, or FDA. They review that data and then they make a decision as to whether or not to approve it. If it's approved, that means insurance companies should pay for that drug. But it's only approved in specific indications, and that indication is based on the study population. So if a study was done in patients with newly diagnosed disease, it will be approved in newly diagnosed disease. If the study was done in relapsed disease, it will be approved in that setting. And these therapies have only been studied and approved in relapsed to refractory multiple myeloma in patients who have had at least four prior lines of therapy. A line of therapy might be the initial induction. Another line of therapy might be a stem cell transplant. Another line of therapy might be maintenance and so on. Importantly, those lines of therapy need to include a proteasome inhibitor such as bortizomib, carfilzomib, or hexazomib, an immunomodulatory drug such as linalytamide, pomalidomide, and thalidomide, and an anti-CD38 monoclonal antibody, daratumumab, or esytoxamab. If a patient has met this criteria, then they are eligible to receive therapy and insurance companies should pay for it. So, bispecific antibodies are administered subcutaneously. This means an injection under the skin. It's usually in the abdomen. And it is given over a few minutes, so it's not a long infusion or injection. It's unique in that it does require a step-up dosing. Step-up dosing means we start at a low dose and then we administer a higher dose, followed by a higher dose, and that gradual administration is necessary to observe any side effects. We would rather have side effects on a lower dose first that we can mitigate with treatment rather than start at the full dose immediately. These step-up dosing are given in the hospital because it requires close monitoring. And the duration of that hospitalization depends on the drug. So, toclistumab and talcuitumab require a seven-day inpatient hospitalization. Where on day one, three, and five, the drug is administered. The other days it's just observation. After 48 hours from the fifth day, the patient is doing well, no signs of cytokine release syndrome, they can go home. Elronanumab is different in that it requires just two inpatient step-up doses. And the patient may go home 24 hours after the third dose. So four days of observation. The subsequent full doses are then given in the clinic outpatient. So no hospitalization needed. And the frequency of those can be every one to two weeks. And I will explain on the next slide when we would give it every two weeks. In patients receiving talcuitumab, the full dose depends on if you're getting it weekly or every other week. The higher dose is for every other week. Now during the inpatient hospitalization, in addition to receiving this drug, a patient would also receive pre-medications before the injection to reduce adverse effects. These are dexamethasone, Benadryl, and Tylenol. If the patient is doing really well after the step-up dosing, these pre-medications may be discontinued. So I mentioned that the frequency of the medications can be given weekly or every other week. So the FDA recommends that talcuitumab be given every two weeks in patients achieving a complete response, or better, for more than six months. A complete response means no detectable monoclonal protein in the blood. Alunatumab is very similar, although the threshold is a little bit lower. So patients may go to every two week dosing if they've achieved a partial response. So at least a 50% reduction in the monoclonal protein, or better, at six months, and with a maintained response of at least two months. Now talcuitumab is unique in that it can be given every two weeks from the onset. Doesn't require a weekly dosing. This is because it was compared every other week to weekly in the initial trial, and the efficacy was found to be very similar, no significant difference. So if you were my patient, I would recommend the every other week dosing because of its convenience. How long do you receive these therapies? It's recommended to receive them for as long as it's working. So it'll tell disease progression, or if you're experiencing toxicity, it should be discontinued. There are adverse side effects associated with bispecific antibodies. The most common is cytokine release syndrome, or CRS for short. I'll talk more about what that means on the next slide. So 72% in talcuitumab, 58 in alorantumab, and 77% of talcuitumab patients experience this side effect. The next most common are reduction in blood counts. Those are neutropenia, anemia, thrombocytopenia. Those can be managed with blood transfusions, or we can give growth factor injections. The next are gastrointestinal side effects, or diarrhea, nausea. The next are fever or fatigue. Less commonly, patients will have some soreness or redness at the site where the shot was given. Headache may occur, cough can occur, and fortunately neurotoxicity is uncommon, but it is seen between 10 to 15% of patients in these trials. So what is cytokine release syndrome, or CRS? It's an inflammatory condition caused by an immune system that is excessively revved up. Symptoms are fever, flu-like symptoms that might be muscle soreness, chills. Patients may have low blood pressure. If we were to check their blood, we would see elevated inflammatory markers. They might have signs of organ damage that can be reversible, and there can be some cognitive dysfunction associated with it. Another type of syndrome called immune effect or cell-associated neurotoxicity syndrome, or ICANNs for short, is when patients may experience confusion, visual or auditory hallucination, language or speech dysfunction, headache, tremor, seizure, and fine motor impairment. Because of these toxicities, which again are rare around 10% of cases, we do neurologic examinations regularly in the hospital so patients will be woken up at night and be asked to write down a sentence or ask questions about where they are just to make sure that they're not experiencing these toxicities. But as I mentioned, CRS is common, and so we have very good algorithms for treating it. It's pretty routine for us right now to be able to treat these symptoms. So here's our algorithm, and I've just made it very simple here for you. If you have a fever alone, nothing else, then we give Tylenol, and the fever usually goes away. If you have fever that persists for more than 24 hours, or you have fever with a reduced blood pressure, or you have fever needing oxygen, or you have moderate to severe neurological impairment, we have a scale that we use for this, we would give Tylenol, we would give IV fluids, and we would give intravenous tosoluzumab, and we would give dexamethasone. So tosoluzumab is an anti-interleukin 6 or IL-6 antibody, and what it does is it binds to the protein circulating in the blood called IL-6, which is made by the immune system. IL-6 is like a chain reaction molecule. When it's present in the blood at high concentration, it causes a chain reaction in the immune system so that the immune system becomes overly activated. By shutting down this molecule, we can dramatically reduce the immune system. So patients will feel better within hours of receiving this drug. But it can only be given in the hospital, not in the clinic. That's why we require that step-up dosing in the inpatient observation. Here are some efficacy results from the clinical trials. One thing I want to point out, I'm going to give you numbers for the three trials, but they're not directly comparable because these were not head-to-head studies. So be aware that the patient populations may differ from study to study. Nevertheless, I'm going to present the data so you can see it all clearly here. So the median progression-free survival is the average time a patient is in remission after they receive the drug. A remission means the disease is still there, but it's in control, it's not causing harm to the patient. The patient's able to live a healthy, normal life except having to come in for those weekly or every other week shots. So the median progression-free survival for Teclistumab is 11.3 months. For Elbronatumab, it's 11.8 months. And for Talquitumab, it's 7.5 months. This is quite good given that these patients had received five, six, or more lines of therapy. They essentially had exhausted all the best myeloma treatment when they enrolled in this study. In other studies like this, we don't usually see this long of a progression-free survival. So I interpret this data to be excellent. So that's the duration of response, which I think matters most. But there's also the depth of response, which is how much the disease has been eliminated since starting the treatment. Here are the different categories. So you have complete response, which means your monoclonal protein is zero. A very good partial response, you've had a 90% reduction in your M protein. A partial response, meaning a 50% reduction. And then a progressive disease is what we don't want. That's when the protein increased by 25%. So the CR rate was 39% for Teclistumab, 35% for Elbronatumab, and 23% for Talquitumab. The very good partial response was 19% for Teclistumab, 21% Elbronatumab, and 33% for Talquitumab. Partial responses were 4%, 5%, and 13%. You add up these three responses and you get the overall response. So these overall responses were 60-70%, which is really outstanding. Fortunately, we have come up with ways that we can prevent cytokine release syndrome. So here I'm going to report some data from a recent publication from our group at the University of Miami, where we investigated using tocilizumab or anti-IL6 before the bispecific antibody infusion, Teclistumab. So only Teclistumab was studied. The results from our study is in the final column titled Present Study. Other studies have also looked at this, and those are in the first four columns. So by giving tocilizumab just prior to Teclistumab, the cytokine release rate was just 13%. Compare that to 72% in the clinical trials, a significant improvement. Other studies doing something very similar saw cytokine release rates of around 29% and 36%. As a result of these findings, we now routinely give tocilizumab prior to bispecific antibody therapies at our institution, and we're seeing very low CRS rates. Unfortunately, infection and low immunoglobulin levels are common in patients receiving bispecific antibodies. Infection occurs in about 47% to 76% of patients. Low immunoglobulin or low antibody levels occur in 75% to 87% of patients. The low immunoglobulins is because normal plasma cells are also targeted in the treatment, and these plasma cells are needed to make the immunoglobulin. Remember, immunoglobulin is needed to help fight infection. So to prevent infections, what we do is we give all of our patients who are receiving bispecific antibody levofloxacin, Bactrim, and acyclovir. These are antibacterials and antiviral therapies. They're given orally. Many patients may have already been receiving them prior to starting this treatment. We also check in the blood in IgG level, immunoglobulin G level. If it's less than 400, we recommend intravenous immunoglobulin or IVIG. This is immunoglobulin molecules from blood donations. You can extract those immunoglobulin molecules from blood donations, concentrate them, and give them to patients. I'm going to touch a bit on potential mechanisms of resistance of bispecific antibodies that may be relevant to you all. In this study that include researchers from our group at Sylvester identified that there are mutations or complete deletions of the BCMA protein in the cell that may occur even before the infusion is given. If it's not before, then it can be acquired during the therapy. If the BCMA protein is butated or completely deleted, then the therapy will no longer recognize the myeloma cells. Perhaps in the future, we will be looking at the gene detection level in patients prior to receiving bispecific antibodies or other B cell maturation antigen directed therapy so that we can make sure that the treatment is going to work before we put the patient through all of that trouble. Here in my final slide, I'm just going to mention some of the bispecific antibodies that are under development. This is a very exciting field. There are lots of treatments in development. The three that I've listed at the top are being studied at our institution. We have open clinical trials. If you think this is interesting, you're welcome to see one of our faculty member. The first is ABBV383. This targets two different BCMA domains. A potential advantage of this, if you have a mutation in BCMA, that one of the domains no longer is recognizable. Perhaps the second domain may be targetable by the antibody. It's administered intravenously and once a month. So it might be more convenient to get it less frequently, but it does require an intravenous infusion. There's no step-up dosing, but it does require 24 hours of inpatient observation. And cytokine release rates are very low, 57%. Linvoseltimab is another investigational bispecific antibody that targets BCMA. It's administered intravenously, initially weekly, but then it can be reduced to monthly. Next is ISB1442. It targets two proteins on myeloma cells. One is CD38, the same protein recognized by daratumumab, and the other CD47, the don't-eat-me protein. And it's called don't-eat-me because when cancer cells make that protein, the immune system doesn't eat it, doesn't engulf it or phagocytose it. Instead, they stay away. But by blocking that don't-eat-me signal, then the myeloma cell is no longer considered unedible and the immune system chomps down on it. It's administered subcutaneously weekly, has a low CRS rate of 50%. And lastly, I mention this one because it binds to a different target. Sevastimab binds to FCRH5, and this is another exciting target in myeloma. Dr. Green may speak about it. There are CAR T-cell therapies targeting this. And it's administered intravenously every three weeks for a year. I will end here with a picture of our faculty at Sylvester. We have a very big group of clinicians, scientists, and others who are all working to find a cure for multiple myeloma. It was a pleasure speaking with you all today. Thank you for your attention.