Crizanlizumab is a monoclonal antibody treatment to reduce the risk of a sickle cell crisis. You can tell because the name ends in “mab”. There are a lot of “mab” drugs coming onto the market in the last few years. One might be tempted to think that this is a new technology, but it was first developed in 1975. There was a long road of development from the first monoclonal antibodies to the current crop of treatments, and it is a good reflection of the relationship between cutting edge science and medicine.
Crizanlizumab is FDA approved for the treatment of a sickle cells crisis and is given as a monthly IV infusion. Like all mabs, it is an expensive treatment, and this remains a limiting practical factor for monoclonal antibody treatments. However, clinical trials show that regular treatment is efficacious in reducing sickle cell crisis by about 60% – “The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo.”
Sickle cell disease is a genetic disorder of hemoglobin which can cause red blood cells to become stiff and misshaped, going from a flexible coin shape to a rigid sickle shape. This can then lead to the formation of clumps of red blood cells which block blood flow, resulting in a painful sickle cell crisis. Having almost two fewer hospitalizations for sickle cell crisis per year could make crizanlizumab treatment cost effective.
Crizanlizumab is a “humanized anti-P-selectin monoclonal antibody” that binds to the protein P-selectin on platelets and the inside walls of blood vessels (endothelium). This blocks and disrupts an interaction among platelets, red blood cells, sickling red blood cells, and the endothelium to reduce the formation of clots that block blood flow and precipitate a sickle cell crisis.
While this is all interesting medical science, why am I bothering to write about it here? I think it’s an excellent representation of many of the realities we face with modern medicine, and it is a useful example of how the relationship between science and medicine works.
The history of monoclonal antibodies is a good example of the complex relationship between scientific advance and the practice of medicine. Essentially these are antibodies that are designed and grown in cells. They are “monoclonal” because they are literally all clones of each other – one clone – so they are identical. Antibodies are “Y” shaped proteins (at least the IgG type) produced by the B-cells of our immune system. They have two binding sites that are highly variable, with each antibody having a specific shape that will fit onto a specific target (called an antigen).
Monoclonal antibodies were first made by injecting a mouse or rat with the protein we want to make antibodies against, then recovering the resulting B-cells from their spleen. These B-cells were then fused with an immortal myeloma cell, to make a hybridoma. These immortal cells could be cultured indefinitely in vitro and will continue to produce the desired antibodies. This technique was developed in 1975. This traditional technique is still used, but there are more modern techniques as well. Bacteriophages can be used to create monoclonal antibodies entirely in vitro. This method is cheaper and faster, and also does not require immunizing an animal and so antibodies against toxic substance can be made.
The first monoclonal antibody treatment was licensed in 1986 – a treatment for acute kidney transplant rejection. However, use was limited because of side effects, mainly stemming from an immune reaction to the monoclonal antibodies themselves, a human anti-mouse antibody response.
It took many more years to develop the technology to the point that monoclonal antibodies could be used routinely as a medical treatment. This is the reason for the “humanized” label when describing crizanlizumab – monoclonal antibodies need to be improved so that they are more human and don’t provoke and immune response of their own. By 2014 there were 30 monoclonal antibodies FDA-approved for use, including for transplant rejection, cancer, chronic infections, and heart disease. Now there are over 100 monoclonal antibody treatments, including treatments to prevent migraines and now sickle cell crises.
Monoclonal antibodies are a good representation of the power of reductionist science. They require an understanding of how biology works at a fundamental level in addition to translating that knowledge into specific clinical applications. While this gives us powerful tools, we also have to recognize the downsides.
First, developing high-tech medical treatments takes time. Monoclonal antibodies are really only coming into their own in the last decade, four decades after they were first developed. There is a tendency to overestimate short term technological advances, and so when new scientific developments are made the press and enthusiasts will often tout their amazing potential. The public is left with the impression that a medical revolution is just around the corner. This leads to inevitable disappointment.
Further, not all new scientific developments pan out as a treatment. Most, in fact, don’t. Early hype that does not put a medical scientific advance into proper context, however, also sets the stage for exploitation and pseudoscience. We have been seeing that for the last two decades regarding stem cells. Early hype about stem cell technology was similar to hyping monoclonal antibodies in the 1970s. In fact, its probably worse, in that stem cell technology is even more tricky, and it seems now that it is going to take much longer to translate into medical treatments. Stem cells may be more of a treatment for the second half of this century. Meanwhile, a host of fraudulent and predatory stem cell clinics have popped up, exploiting the premature hype.
Another reality we have to face is that monoclonal antibody treatments, like most high-tech medical treatments, are expensive. In fact, technology is by far the number one driver of rising health care costs. Sometimes, as with sickle cell disease, even expensive treatments can be cost effective if they reduce hospitalizations, which are themselves very expensive. But often they simply add a new costly treatment. The monoclonal antibodies targeting CGRP receptors and antigens are highly effective treatments for the prevention of migraine headaches but they cost up to $8,000 per year. They improve quality of life and may also reduce lost productivity, but overall they increase the cost of managing severe migraine, which is the primary limiting factor on their use.
In the end we just have to decide as a society how much health care we are willing to pay for. But also we can make choices about how to target our research and development, and perhaps prioritize cost effectiveness as a practical matter.
Despite the fact that high-tech medical treatments come with trade-offs, most people feel they are worth it, especially if they or a loved-one is a beneficiary. Also, no one would argue that they are a replacement for simpler interventions, or basic healthy lifestyle choices. We also have to confront issues of equity of access. But it is better to live in a world with them than without them.