Bispecifics Part 2: Monoclonal and Bispecific Antibodies

Dr. Joseph Mikhael: Monoclonal and bispecific antibodies. What are monoclonal antibodies? Monoclonal antibodies are antibodies that we create in the lab that reproduces the concept of what antibodies do. We've identified many antigens on myeloma cells that include things such as CD38, SLAMF7 and BCMA, or B-cell maturation antigen, and now we have drugs that are specific to each of these antigens on the outside of the myeloma cell that they can hook onto to help destroy that myeloma cell. We call these monoclonal antibodies because they're designed to attach to one antigen on the myeloma cell. Examples of monoclonal antibodies in multiple myeloma include daratumumab, elotuzumab, and isatuximab. These drugs therefore attach themselves to the myeloma cell, avoiding the normal tissues, and trigger the immune system to destroy myeloma cells. What are bispecific antibodies? Bispecific antibodies are similar to monoclonal antibodies, but as their name implies, they have two arms allowing them to attach to two antigens, hence the word bispecific.

It's kind of like having two monoclonal antibodies together. One arm attaches to the myeloma cell and the other arm attaches to an immune cell like a T-cell. T-cells have an antigen called the CD3 antigen, and so the bispecific antibody hooks onto that T-cell or may hook onto a natural killer cell. By doing so, it can activate the T-cell or the natural killer cell to directly engage the myeloma cell and kill it. Furthermore, the activation of the T-cell or the natural killer cell can trigger it to recruit even more cells in the fight against myeloma. Thus, bispecifics work with your immune system to destroy myeloma cells. Furthermore, these drugs have proven to be very effective as monotherapy, meaning that they work by themselves, not necessarily in combination as opposed to many other therapies that we always give in combination. This is genuinely remarkable.

What is the difference between CAR T-cell therapy and bispecific therapy? When we give bispecific therapy, in some ways it's quite similar to what we do with CAR T-cell therapy. In the process of CAR T-cell therapy, we take T-cells out of a patient and manufacture them in the lab and attach a receptor to them so that they can easily recognize the antigen on the outside of the myeloma cell. This is why we call it CAR T where the CAR stands for chimeric antigen receptor. So chimeric antigen receptor T-cells are what we give back to the patient after in the lab we've created them and even multiplied them. We infuse them back into the patient, and then these highly trained T-cells can now specifically attack the patient's multiple myeloma. The receptor on the outside of the T-cell recognizes that antigen on the surface of the myeloma cell. Typically, now we use the BCMA antigen, the B-cell maturation antigen, but other targets are being developed for CAR T-cell therapy.

It's also important to note that CAR T-cell therapy requires a complex process of collecting T-cells, manufacturing them in a lab which often takes four to six weeks, and then re-infusing them into the patient, which we usually do in the hospital. By contrast, with bispecific therapies, we just take these drugs, if you will, off the shelf and directly give them to the patient so it can start acting right away. Those bispecific antibodies have two arms as we've described. One that binds to the cancer cell, the other that binds to either a T-cell or a natural killer cell to engage it to destroy the myeloma cell.