CLL INTRODUCTION: Antibodies

Monoclonal antibodies are exciting agents (drugs) being used to treat cancer as well as other disorders. One of the advantages of using monoclonal antibodies in treating cancer is that they provide targeted therapy. There are multiple proteins on the surface of the CLL cell, numbering in the thousands. Usually a specific protein is designated by the letters CD and a number. A monoclonal antibody is an agent that has been designed to bind specifically to a CD protein on the surface of the CLL cell.

The two antibodies that are often used in treatment of CLL (rituximab and alemtuzumab) bind to different surface proteins. Rituximab (Rituxan in U.S., Mabthera elsewhere) binds to a protein called CD20, which is present on a subset of lymphocytes, namely B-lymphocytes. Alemtuzumab (Campath) binds to CD52, another protein that is present on B-lymphocytes as well as T lymphocytes.

All of the monoclonal antibodies which are commercially available, i.e. approved by the FDA, for various indications, are chimeric antibodies. The original antibodies were raised in mice and had a mouse protein sequence which is different from the human version of the protein. Subsequently, when these mouse monoclonal antibodies are given to humans, humans recognize them as foreign and then make antibodies to the therapeutic antibody. If the patient makes antibodies to the therapeutic antibody, then the therapeutic antibody is neutralized and not allowed to reach the disease target, such as lymph nodes or bone marrow. To circumvent this, researchers manipulated the protein sequence of the therapeutic antibody so the vast majority resembles the human sequence. This usually prevents patients from developing antibodies that would soak up (neutralize) the therapeutic antibody.

There are several ways an antibody binding to the cell surface protein can result in cell death. One mechanism is that once the antibody binds to the CLL cell, the immune system of the patient sees it as a foreign body. This is because we normally have antibodies in our system, which help protect against infection by binding to bacteria, etc. When the immune system sees a cell with an antibody bound to it, this usually clues the immune system to remove that cell (because the immune system thinks it is an invading infection) using a set of complement proteins and immunity cells. In addition, in some systems just the binding of the antibody to the antigen or surface protein triggers a death signal to the cell.

Data with both alemtuzumab and rituximab suggests that using antibodies in combination with chemotherapy may be synergistic. That is to say that the antibody and the chemotherapy potentiate each other and make each one more effective than if used alone. The most common side effects with antibodies used to treat CLL are infusion related side effects, generally seen with the initial doses. These typically are fever and chills, but other side effects can be seen such as nausea and rash. Occasionally, patients have a more severe reaction such as a drop in the blood pressure or shortness of breath. Usually these reactions can be treated immediately. In addition, as the treatment continues and a patient's body gets used to having these foreign proteins (the therapeutic antibody) administered, the side effects usually lessen. There are some clinical trials exploring the use of alemtuzumab as a subcutaneous (under the skin) injection rather than the standard intravenous infusion. Preliminary data suggests that most of the infusion related side effects are markedly diminished with the use of the subcutaneous administration. When given in this way, the most common side effect are skin reactions, which are typically large areas of redness that are not painful and, like the IV infusion side effects, the skin reactions tend to go away with continued administration of the drug. Because the target of alemtuzumab, CD52, is also present on T-cells, alemtuzumab depletes more lymphocytes than Rituximab and this can lead to more infections. Thus, all patients receiving alemtuzumab need to receive prophylactic antibiotic to prevent Herpes infection or a specific type of pneumonia called PCP. Also a virus called CMV (cytomegolovirus) can be reactivated.

Since there are many other proteins on the surface of the CLL cell, other antibodies are currently under development that target different proteins. None of these are commercially available but clinical trials are ongoing to investigate the activity of these monoclonal antibodies either alone or in combination with chemotherapy. We will surely see more monoclonal antibodies becoming available in the future.

Antibody-based treatment strategies provide an opportunity for targeted therapy. The antibody binds to cell surface proteins inducing cell death.