“And now he had acquired the wisdom to admit that sometimes he experienced his disdain for “weak, sick people” because he was frightened by any suggestion that he could ever become that.”
― James C. Coyne
The theme of the day, much like a heading in a restaurant’s menu, is monoclonal antibodies. I will try to explain why we use these proteins to prevent and treat disease. As we begin, I must emphasize that this field is in its infancy. The reader must be willing to accept that tomorrow what you read today may be outdated.
As living things evolved, they developed the capacity to reject invaders. These unwelcome intruders, almost all of them microscopic life forms (that we almost certainly evolved from), are everywhere. In most instances we have found ways to coexist with them. Our mouths, intestines, and skins are teeming with germs, many of which are useful to us. In the absence of intestinal bacteria, we would have constant diarrhea, and we would not be able to make the vitamin K that is essential for blood clotting. Many experts believe that these germs, in the right combination, are an important reason that most people avoid getting autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease.
Trouble begins when a germ that does not have one of these cooperative agreements with us decides to invade us. This can happen when we eat contaminated food, or when we inhale particles that carry unwanted germs. We can also get sick when germs that belong in one part of our bodies (like Staph in our skins, or E.coli in our bowels) somehow find a way to move to an organ that is not prepared to handle them. A skin laceration or abrasion can offer a port of entry to Staph; this breach can lead to serious problems and even death. The same happens when E. coli finds its way into women’s bladders: a painful UTI will ensue.
Once the invaders gain access to our systems, the immune system goes to work. The innate immune system (the oldest in evolutionary terms) has specialized cells all over our bodies that are trained to detect “stuff” that does not belong to us. These cells latch on to an invader and send out a chemical message into the bloodstream (and surrounding tissues). Within minutes specialized soldiers materialize. Their job is to gobble up all or parts of the germ. Once inside these cells the germ is cut into smaller pieces, which are promptly sent out into the cell membrane (the technical term is “expressed”), where they protrude as dozens of tiny antennas.
As we go up on the evolutionary scale, the adaptive immune system comes into play. More chemicals are released. Again, within minutes, hundreds of immune cells called T cells surround these antennae to determine what ingredients are the building blocks for these germs. The T cells then train themselves to swallow these germs (“Killer” T cells). Other T cells teach a different kind of cell, called a B cell, to make antibodies against the germ (“Helper” T cells).
In most cases, the parts of the germs that provoke an immune reaction are proteins. All the antibodies that stick to germs are proteins. The part of the germ that produces an immune reaction is called an antigen.
You must think of this process as something that takes place in three dimensions. When B cells are properly stimulated, they make dozens of different antibodies to the germ. This makes sense, since the germ’s proteins are large molecules and have numerous spots that are available for “mating” with an antibody. Some of these unions are fragile and easily dissolved. Other antibodies stick to the germ’s proteins as if their life depended on it. Those bonds are almost impossible to break (within a human body). These are called “high-avidity” and “high-affinity” antibodies.
In ways that we do not understand well, our bodies learn, quickly, which one of the dozens of the antibodies that have been made are the high avidity, high affinity ones. The B cells that make the weak antibodies are told to kill themselves (the technical term for this process is called “apoptosis”). The B cells that make the good stuff are told to have millions of babies; all of them programmed with the same instructions to generate powerful antibodies. The descendants of one of these good B cells are said to be a “clone” of that cell. They are identical and indistinguishable from their mother.
Antibodies that attach themselves to invaders are classified as “binding” and “neutralizing.” As the names suggest, the binding antibodies stick to the invaders, but do little to counteract infection. This can be because they bind to parts of the virus (in this case) that the virus does not need to invade our cells. Or maybe the binding is not tight enough to last. Neutralizing antibodies stick to parts of the virus that are essential for the virus to be able to make more copies of itself. Those are the ones that we want to make in industrial amounts.
There are several ways that this can be done under factory conditions. Regeneron, the company that makes the antibodies that the president received, uses mice whose genes have been changed to closely mimic a human antibody factory. They are injected with the “spike” protein that the virus needs in order to invade our cells. The mice go to town making antibodies that look like and behave as human antibodies. Regeneron has chosen two of these proteins to produce at large scale. This is the “cocktail” that the president received.
The other pharmaceutical firms that did this research do not have the same antibodies. At least I think that it is very unlikely that all of them have decided to “clone” the same antibodies. In order to increase the odds that their product will work, they cannot settle on a single antibody to clone. They have a “cocktail” of two or more that they have done human tests on.
It is unlikely that they will package a dozen antibodies into these cocktails, because it is awfully expensive and time-consuming to make large amounts of even one. It is also unlikely that they have stopped at just one mono (as in “one”) clonal protein, because if that one they have chosen is ineffective, they have wasted hundreds of millions of dollars in this endeavor.
Just because an antibody sticks tightly to a germ does not guarantee efficacy when it is used for treatment. The combination of antigen and antibody must be recognized by still other immune cells. If the three-dimensional shape of these antigen-antibody globs are such that they are poorly identified by these cells, the antibody may prove to be useless. Therefore, we need more than one of these monoclonal antibodies.
There are many pros and cons to these potential new treatments. They are human proteins, which makes them unlikely to provoke an allergic reaction. Most antibodies hang around for 6 weeks; some more. This would provide protection for your long-dreamed-of vacation with little need to worry about contagion. You can use them as preventives and as treatments: we could make high-risk people immune for a short while, or until an effective vaccine is found.
On the negative side: they are darn expensive to make. And difficult. No way that at any time soon there will be billions of doses available. They must be injected (although they are talking about nasal preparations), which means needles and specially trained employees to administer them. I assume that they will need to be refrigerated, maybe frozen, which will make administration in remote areas very inconvenient. They do nothing to stimulate killer T cells, which are an important reason that vaccines work so well. They wear off, so that repeated expensive injections would be needed to keep up the patient’s immunity until an effective vaccine is available. Some research is being done on llamas, which make smaller antibodies (called nanoantibodies), which last a lot longer and could potentially be given intranasally.
Still and all, the fact that we have several viable (albeit still experimental) alternatives for treating this virus months after its appearance ranks as one of the greatest scientific and logistical successes of all time. We must pat ourselves, and the world´s scientists, and many international governmental agencies, on the back. Well done.
