Monoclonal Antibodies Should Be The Last Resort

Monoclonal antibodies are the latest hot drug. They are very expensive to produce, usually offer only limited benefit if any, and often have unexpected consequences.

Monoclonal antibodies are an attempt to engage the adaptive immune system in the fight against some disease. The adaptive immune system marks a pathogen with antibodies. Antibodies are small “Y” shaped proteins manufactured by B-type white blood cells. There are literally millions of different ones on patrol, each designated to recognize a different pathogen—bacteria, virus, or other foreign material. The antibody usually disables it and marks it for destruction.

This works very well, but the adaptive immune system is very powerful. If it recognized our own stuff as a pathogen, it could kill us in minutes. Autoimmune diseases are examples of these. The antibodies are randomly generated, however, the ones that match up to body tissue are eliminated before they can cause trouble—how isn’t exactly clear.

Monoclonal antibodies are an attempt to ‘trick’ the adaptive immune system into attacking something that it wouldn’t otherwise attack. Before plunging  into this, we should ponder why the immune system is not attacking a pathogen. Normally, the adaptive immune system is quite active in this regard, and able to spot just about anything that might harm us. One possible answer is that the pathogen looks too much like ‘us’. This could, of course, be the case for a tumor, which is us.

Cancer has thus far been the principle therapeutic application of monoclonal antibodies. Since cancer presents a rather ambiguous case to the immune system, this may be why the success has been rather sporadic. Typical drugs of this class are: gentuzumab, alemtuzumab, rituximab, trastuzumab, and so on. The all end in mab, (for monoclonal anti body).monoclonal

The mono part means they are specific to a certain pathogen. They are typically made by infecting a mouse with the pathogen of interest. Let’s say is was a tumor from a human who’s own immune system was producing no antibodies to fight it. When the tumor bits are injected into the mouse, antibodies are produced, and these may be retrieved from the mouse. But there are two problems. First, the antibodies are mouse, not human, and second, there are a variety of different ones in the retrieved mix. This mix is said to be ‘polyclonal’. A number of tricky steps are required to obtain human compatible antibodies that match the desired pathogen. At the end of the process, a reproducing cell will be obtained that always produced the desired antibodies.

The next step is to introduce the antibodies back into the person the original sample was obtained from. Herein danger lurks. First, are they really the right ones. They were right for the mouse, but is that going to translate? Second, the body wasn’t making these antibodies or else wasn’t using them. Why? Were they too close to healthy tissue?

Needless to say, each dose has to be specifically tailored to each patient, which makes mass production difficult, and causes the cost of these drugs to be enormous.

So far, monoclonal antibody therapy has been disappointing. One reason is that they tend to bind to various proteins that aren’t associated with the target pathogen. They also frequently don’t do a very good job of binding the pathogen itself.

The other side of the coin is the nature of cancer itself. Cancer involves a sequence of mutations, and evading the immune system is one of them. Indeed most beginning cancers are recognized and destroyed by the immune system itself. A cancer that has evolved into a tumor has already accomplished this step, and, in fact, in most cancer patients, the antibodies that can recognize the cancer are already present, they simply aren’t doing anything. Most likely the cancer has tricked them and will likely trick the newly introduced antibodies as well.

With these observations, the therapy devolves into massive introduction of antibodies in hopes that some of them will bind to the tumor. But massive doses of antibodies, especially antibodies that can attach to healthy stuff, is problematic as well.

In spite of setbacks, there is continued interest in monoclonal antibodies. Currently there are several hundred drugs in clinical trial.

We hope we are wrong, but suspect that trying to get the immune system to do something that it could be doing, but for some reason doesn’t want to do, is not going to prove successful.

The latest research direction is Alzheimer’s, and various drugs are being developed to go after the beta-amyloid deposits characteristic of the disease. This seems odd, as the beta-amyloid seems to be a side effect of the primary cause, a glucose-insulin overload. There is some evidence that it is, in fact, a protective reaction to the overload. It will be interesting to see how this one turns out.

  2 comments for “Monoclonal Antibodies Should Be The Last Resort

  1. Jim
    May 13, 2015 at 6:47 am

    This is all so intriguing how we attempt to manipulate such intricate and extremely complex systems our bodies have evolved from for millions of years. Our species literally lives day-to-day with organisms (inside and outside of our bodies) as well as aberrations presumably from within our own cell make-up, that are fighting for existence and potentially their next evolutionary leap. It makes me wonder where our species will branch to next. As with the mitochondria, will some yet unknown cell-line incorporate itself into our genome offering a “new breed”? Or do I just watch too many science fiction movies?

    • May 13, 2015 at 8:23 am

      What? Too many science fiction movies? The future is science fiction. Imagine, just imagine. Dr. Mike

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