While most of our genes are designed to make just one protein, some immune genes can be shuffled to make an astonishing array of different proteins called antibodies. Flavius Martin, Amgen’s vice president for oncology and inflammation research, explains these versatile genes and their potential to lead to a COVID-19 therapy.
How is the DNA in our immune system different? How does it protect us from so many different threats?
B cells and T cells are classes of white blood cells that have special properties compared to other cells in the body. They are equipped with machinery that gives them this almost magical ability to diversify the particular proteins they make. By combining different pieces of DNA, they can create an almost unlimited variety of receptors and antibodies. There is a constant war between our immune system and the microbial world, and this special ability of our T cells and B cells has evolved to keep up with the diversity of viruses and bacteria we might encounter.
How many different types of receptors and antibodies can these cells make?
In theory, the number is almost unlimited, but in any given individual, it’s in the billions. In addition to the machinery which gives rise to this enormous diversity, B cells have another amazing process which occurs after a B cell encounters a microbe it can bind to. When that happens, the B cell starts to rapidly mutate to try to adjust its fit and become even better at recognizing the microbe. When specific B cells and T cells are very successful at fighting a particular virus or bacteria, they produce memory cells to protect against future infections from the same microbe. If you’re exposed again, the memory cells can respond in a couple of days by making antibodies that help the body fight off the infection.
Are some antibodies better than others at fighting a dangerous virus like SARS-CoV-2?
The immune system tries to make every antibody that it can make against a virus, but various individuals do it in different ways. First, it depends on how healthy your immune system is. It’s more robust when you are younger, and it could be compromised if you have an illness like cancer or autoimmune disease, and you may be receiving treatments that suppress immunity. It also depends on which antibodies you generate and you have available to fight the virus. Some antibodies are just binders—they can bind to the virus but they are not very good at neutralizing its activity. Others are very good at eliminating the virus or virus-infected cells.
When you are looking to make a potential neutralizing antibody therapy, as Amgen and Adaptive Biotechnologies are now doing, the goal is to find very special antibodies that can neutralize a broad panel of virus strains that have evolved in different parts of the world and different individuals. The antibodies we are looking for are a lot rarer than one in a million—we have to go through billions and billions of cells in an efficient way. But together, our two companies have the right capabilities to potentially do this.
Can you briefly describe those capabilities?
Adaptive Biotechnologies can do very deep DNA sequencing on large numbers of antibody-making B cells taken from individuals whose immune systems were able to defeat COVID-19. Adaptive can do this rapidly and on a massive scale by using artificial intelligence and machine learning to analyze the results and identify the genes that might make potent antibodies to SARS-CoV-2.
Once we find these genes, we need to make and screen thousands of antibodies that bind the proteins on the coronavirus that we want to target. At Amgen, we have a deep understanding of the immune system, which will help us to make technical decisions involved in designing and running large antibody screens. We are also very strong in antibody engineering and drug development. For example, we know how to alter the design of antibodies in ways that make them easier to manufacture or help them to work longer in the body.
And finally, we have our deCODE Genetics subsidiary in Iceland, which is sequencing the DNA of the virus from many individuals in Iceland who has been infected. They have the analytical capabilities to integrate this information with SARS-CoV-2 sequence data collected around the globe. That can help us to figure out which parts of different coronavirus proteins are the least likely to be mutated, which will guide us in selecting the antibodies to advance. In the end, we may need a cocktail of several antibodies to try to cover the majority or all of the viral strains we have seen.
In addition to sequencing the virus, deCODE also has in-depth genetic data on the Icelandic population, including individuals who have been infected with SARS-CoV-2. Those genetic insights could be very helpful in answering all sorts of questions, such as determining if certain genes might make you more likely or less likely to develop severe complications if you get infected. The power of putting the viral genetics together with the human genetics could be very useful in guiding drug development and helping societies to fight this terrible illness.
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