If you ask the general public or members of the press what the most exciting or powerful medical developments have been in recent decades they will likely mention things that are more hype than reality. Stem cells, antioxidants, superfoods, and magnetic therapy might get a mention. CRISPR will also likely get mentioned, and this is a genuinely exciting technology, but still in its infancy as a therapeutic tool. l doubt many non-experts would put at or near the top of their list monoclonal antibody therapeutics, even though this technology has been quietly revolutionizing medicine in the last decade.
Even as a physician its possible to have not noticed the scope of change that has occurred. There are new monoclonal antibody (mAb) products in my subspecialty, but it takes time to notice that every subspecialty seems to have them. What’s going on?
The first monoclonal antibody was created in 1975, and the first therapeutic product was licensed in 1986. Yet mAbs are only now coming into their own as a mature medical treatment. The basic technology involves the isolation of a single B cell, the type of cell in the immune system that makes antibodies. Antibodies are proteins that have two binding sites with variable affinity for another protein or substance, called an antigen (a target binding site for an antibody). Normally an immune response involves producing lots of B cells with variable antibodies, a sort of “shotgun” approach to immunity. This blankets possible antigens, and then gets more specific as the immune system learns how to better target the invading organism or substance. Such an immune response is called polyclonal, or many-cloned, because many different types of antibodies are produced.
A monoclonal antibody, or single clone, involves isolating a single B cell (which makes one specific clone of antibodies) and then reproducing it, so that you can make a lot of a single clone of antibodies. The initial technique for doing this was injecting an animal, such as a rat, with an antigen in order to produce an antibody response, then isolating a single B cell that produces an antibody against that antigen. This B cells is then hybridized with an immortal B cell, taken from a cancer such as myeloma, but one that does not produce antibodies of its own. You then hopefully have an immortal B cell that creates the antibodies you want. You then culture that cells for mass production.
The basic technology existed almost 50 years ago, so why are we only now seeing so many mAb therapeutics? Because I am glossing over a lot of complexity. First, you have to select a B-cell that produces an antibody with the desired affinity that does not also cross-react with other proteins you don’t want (causing side effects). Also, because an animal is used, there are non-human protein sequences on the mAbs that can trigger their own immune response, an immune reaction against the mAbs themselves. One workaround for this was to partially humanize the mAbs, joining the part of the antibody with the desired affinity to a human antibody base. It also took decades to develop the technology to the point where it was cost effective to mass produce mAbs as a pharmaceutical product.
The technology to mass produce human or humanized mAbs with the desired affinity is also only half of the equation. You also need to identify a therapeutic target – what are you going to target the mAbs against. This requires research into the mechanisms of specific diseases. Of course this was already happening. Essentially now, when a therapeutic target is identified, pharmaceutical companies can develop traditional drugs that chemically react with the target, and/or they can develop mAbs with affinity for the target.
Essentially we crossed a fuzzy threshold where mAb technology has progressed to the point that it is medically and economically feasible to quickly develop and mass produce mAb products. This technology also allows for a level of personalized medicine. You can identify specific targets on an individual patient’s cancer and then target that. To put recent progress into perspective, in 2014 there were 30 mAbs approved by the FDA (and this is after they already started to take off) and the global market was estimated at $30 billion. In 2022 it was estimate at $188 billion, and is growing fast. As of December 2022, the FDA has approved 153 mAbs, and there are 140 products in late stage development.
As a therapeutic choice there are positives and negatives to mAbs. First, they are not chemical drugs, so they don’t interact with other drugs, and they don’t have to be processed by the liver or eliminated by the kidneys like many other drugs. They can also be highly specific in their affinity, which can reduce the side effect profile. Because they are proteins they are given as injections or IV infusions. This has both advantages and disadvantages. Getting a self-injection once a month, for example, may be preferable to many people than taking a daily pill. This also can improve compliance. However, some people are needle-phobic.
Perhaps the biggest disadvantage of mAbs is that they are expensive. Even though the cost has come way down, it may still cost thousands of dollars per year for mAb treatment. While the therapeutic potential is great for patients, we are potentially adding billions of dollars to already high health care costs. Insurance companies are pushing back, and it is often challenging to get approval for new mAb therapies. To some extent this makes sense – we need to practice cost effective medicine, and it does not make sense to replace a drug that costs a couple hundred dollars per year with one that costs 6-7 thousand per year for a small incremental improvement. Costs are likely to come down as technology and mass production improve, but mAbs are likely to remain relatively expensive for years. In a way, it’s a good problem to have, but it still is a serious issue.
Monoclonal antibodies are a fascinating technology that has been around for a long time but is just now really coming into its own as a therapeutic tool. They show the power of scientific medicine, but also the challenges, and how long it can take to go from new discovery to have a large impact on the practice of medicine. I find it interesting that attention and media hype is often aimed in the wrong direction. Perhaps the mAb “revolution” was too slow, or too diffuse, to make sexy headlines. The story of mAbs also stands in contrast to many hyped but not legitimate treatments – new treatments do not come out of nowhere. They have a long history, and involve the work of countless scientists and organizations working over decades. Understanding and appreciating real scientific developments makes it easier to recognize the fake ones.