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How Monoclonal Antibodies Work

Posted by Frederick Wasti
Sep 02 2012

In Part A of my Dana-Farber clinical trial, I had frequent (weekly) infusions of Ofatumumab, a monoclonal antibody. In Part B, I have very frequent (three times each week) injections of Alemtuzumab (also a monoclonal antibody), along with occasional (once a month) infusions of Ofatumumab. And, in Part C, I will again receive, although less frequently, both Alemtuzumab (twice a month) and Ofatumumab (once a month). So, it is clear that these two monoclonal antibodies are both important components in my treatment for CLL.

But, just what are monoclonal antibodies, and how do they work? And, perhaps more importantly, how are they different from the "usual" chemotherapy drugs? I'll try to cover the "what is a monoclonal antibody?" question in a future post, but I'd like to try to start answering both the "how does a monoclonal antibody work?" and "how is a monoclonal antibody different from the 'usual' chemotherapy drugs?" questions right here.

First, please keep in mind that "regular" chemotherapy drugs are very non-specific. In general, chemo drugs are designed to work on all rapidly dividing cells, and cancer cells are indeed rapidly dividing cells, so admittedly that does seem to make some sense. However, there are many other cells in the body that divide rapidly, too, such as skin cells and the cells that line the digestive tract, and they (as well as certain other sensitive cells) are also affected by "regular" chemo drugs. (As an example of this, hair loss due to chemotherapy is quite common, as we all know, and is due to actively dividing hair follicle cells in the skin being adversely affected by "typical" chemo drugs.)

Furthermore, many chemo drugs work their "magic" by interfering with DNA and/or RNA in actively dividing cells, and such "magic" can result in significant unintentional genetic side effects, even including triggering additional future cancers. (Of course, when someone is suffering from cancer, to fight it with a drug that might cause another cancer sometime in the future, in order to hopefully stop the current cancer in its tracks, is generally considered a fair trade-off.)

[I have previously covered some aspects of drug specificity and non-specific collateral damage (please see "Dr. Ehrlich's Magic Bullet" from 5/12/12 and "The Father of Non-Chemotherapy" from 5/22/12).]

However, monoclonal antibodies are, in comparison, very specific. They are still not quite perfect drugs (medical science is still searching for elusive perfect "magic bullets" for many, many diseases), but they do tend to target just certain cells having certain specific characteristics, and (ideally) have little or no effect on at least most other cells of the body. So, let's take a look at how monoclonal antibodies can be used to selectively kill lymphocytes as an entirely relevant example of this technology:

Lymphocytes, under a typical light microscope, appear to be more-or-less round cells having smooth surfaces. However, those apparent smooth surfaces are actually pretty "fuzzy", and much of that "fuzz" is due to the presence of large molecules either arising from or protruding through a lymphocyte's cell membrane. Scientists have determined which particular molecules are found on the surface of lymphocytes (and on other types of cells), and have named (or numbered) these molecules with numerical "CD" names. ("CD" stands for "cluster of differentiation".) Take a look at the schematic diagram of a B-lymphocyte below:

As you can see, a B-lymphocyte (the type of lymphocyte involved in CLL) has several types of CD molecules on its surface. Now, as it turns out, if you have a monoclonal antibody that can recognize and attach itself to, say, CD20 molecules, such attachments could easily interfere with the proper functioning of lymphocytes, either by interfering with cell signaling (as cells do normally "communicate" with each other biochemically), or by bringing about cell death either directly (by triggering the process of apoptosis, a.k.a. "programmed cell death") or indirectly (by otherwise simply interfering with important physiological processes, or by causing other cells to kill such "marked" lymphocytes).

Now, if you glazed over reading the above paragraph (as I did when I was proofreading it - <grin>), the important point to remember is this: If a monoclonal antibody attaches itself to one of a lymphocyte's many surface proteins, doing so will likely hurt or even kill the lymphocyte.

One of the advantages of using Ofatumumab for treating CLL (which involves only B-lymphocytes) is that Ofatumumab attaches itself only to CD20 molecules, and, since CD20 molecules are found only on B-lymphocytes, then only B-lymphocytes are killed when this attachment takes place. (Unfortunately, leukemic and healthy B-lymphocytes both have CD20 molecules, so it is obvious that using Ofatumumab does involve some collateral damage.)

While I do not have a video to share that shows how Ofatumumab kills B-lymphocytes by attaching to their CD20 molecules, I do have a link to a video showing how a similar monoclonal antibody called Rituximab (trade name Rituxan) does so - please click on the image below to view the video (in a separate browser window):

A couple of points related to this video:

1. Notice that it is not clear which of the three illustrated cell death mechanisms is/are actually at work once the monoclonal antibody attaches itself to the CD20 molecule. It could be any one of the three mechanisms, or maybe a combination of them, or perhaps it's something else not even known of yet. However, the bottom line is that the lymphocyte is killed, and that is the important thing in CLL.

2. Although the video happens to feature Rituximab (since it was produced by Rituxan's manufacturer, after all - <grin>), the monoclonal antibodies I am taking (Ofatumumab and Alemtuzumab) do act similarly. The biggest difference is that, while Ofatumumab also attaches to CD20 molecules, Alemtuzumab instead attaches to CD52 molecules, which are found on both B-lymphocytes and T-lymphocytes, so that, even though Alemtuzumab may be even more potent at destroying B-lymphocytes than Ofatumumab or Rituximab, the collateral damage from using Alemtuzumab is unfortunately also significantly greater.

Nowadays, the use of monoclonal antibodies for combating cancers, as opposed to the use of "regular" chemo drugs, is increasing. Of course, because different types of cancers involve different types of cells, and because each type of cell can have distinctive surface molecules, different monoclonal antibodies have to be used to attack different types of cancer cells, as illustrated in the image below:

Well, I hope I have provided here at least an introduction to how monoclonal antibodies work and to how they are fundamentally different from the "usual" chemotherapy drugs. As someone who is trying to avoid "regular" chemotherapy, I do have to say that I am certainly grateful for the development of such wonderful technology.

Categories: Leukemia