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Figuring out how to hack the immune system and make the antibodies we want was just the beginning. Thanks to innovative technologies, we're finding ways to produce safe, effective antibodies for all sorts of uses.

Part 1 of our antibodies series:

Hosted by: Stefan Chin

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For over a century, we’ve taken advantage of the fact that special immune cells called B cells produce these sticky Y-shaped proteins called antibodies after they face a threat.

Now, you might not think stickiness is that big of a flex, but /just/ by sticking to things, antibodies can shut down germs and protect you from getting sick. And we can use their stickiness to spot pretty much anything we want!

A virus. A protein. A hormone. /Whatever/.

That’s why mass-produced monoclonal antibodies have become essential tools in benchtop science and in diagnostic testing, in addition to their medical uses. But all of this relies on having /great/ antibodies that really stick to their targets, or antigens. And /finding/ a great antibody isn’t necessarily easy.

Antibody discovery can happen one of several ways. One option harkens back to the old-school idea of treating people with the antibodies of someone else who’s recovered from an infection. Except, you just want their /best/ antibody.

So, you find and clone the B cell that makes it! There are some slight variations in the methods. But, generally speaking, these single B cell antibody technologies involve pulling B cells from the blood or bone marrow of someone who’s been infected with a pathogen.

Then, you sort through them to find the one that sticks the best. Scientists don’t talk about “stickiness”, though — they call the strength of the interaction between an antibody and its antigen its /affinity/. Once a high-affinity B cell is isolated, researchers can paste its antibody-making genes into cells that replicate really, really quickly.

This allows them to make tons and tons of copies of that antibody! And all that can all be done pretty quickly with a limited amount of antigen, which makes it a great technology to use when you want antibodies for emerging infections— like, say, COVID-19. It’s also been used to develop drugs for other viruses, including SARS and H1N1.

But it’s not perfect. One of the biggest downsides is that you’re relying on a person making good antibodies, which doesn’t always happen. Plus, somebody has to get sick!

Which is why, even to this day, a lot of monoclonal antibody drugs are actually developed in /mice/. Modern-day mouse methods for producing antibodies are surprisingly similar to what doctors did a hundred years ago to make the first antitoxins and antivenoms. You inject a pathogen or toxin into a mouse and wait for it to produce antibodies; those are what become your drug.

But there’s /one/ big difference: the mice used today are a bit more /human/. You see, since the 1980s, we’ve been replacing mouse antibody genes with human ones. So, thanks to a clever bit of genetic engineering, when the /mouse’s/ B cells come into contact with an antigen, they pump out /human/ antibodies.

That lowers the potential for unintended side effects, like developing allergies to the animal proteins. And yet, no human needs to be infected. But it’s not a perfect method.

It turns out that humanized mouse antibodies tend to have lower affinities than purely human /or/ purely mouse antibodies. Plus, even though the immune response creates human antibodies, it’s still a mouse-sized response. And mouse immune systems just don’t tend to react as robustly to things as ours do.

In an ideal world, what you’d want is a way to skip the whole infecting something bit and just quickly screen /billions/ of potential antibodies to find the best ones. …and that’s exactly what phage-display technology does! It relies on viruses that infect bacteria called bacteriophages… hence the phage part. The “display” bit refers to the fact that researchers insert the gene for the sticky ends of antibodies into the genetic code for the phage’s outer coat.

That way, they’re built into the outside, or /displayed/ on the phage, where they can stick to potential antigens. And it turns out we already have /billions/ of different antibody genes that scientists can plug into this system. Researchers have gone through and sequenced /tons/ of B cells from people to create these giant libraries of potential antibodies.

And they continue to add more sequences all the time! So, the idea here is that you create these billions of different viruses, and then you add them all to dishes with the antigen of interest. Then, you rinse.

The phages with high affinity will grab on and hold tight, so they’ll stay in the dish, while any that didn’t stick will get washed away. This process can then be repeated over and over again until you get the very best antibody. Finally, you take the ones that did stick, and you give them bacteria to infect.

And like all viruses do, they /make copies of themselves/— so you end up with enough genetic material to sequence! Then, all you have to do is put the awesome antibody gene into some kind of cellular production system, and you’ve got your super potent drug. With no animals harmed!

Which makes it much cheaper than other methods. Plus, it’s quick and efficient. Researchers can screen billions of antibodies /per week/ to find the absolute best ones.

All of this makes it especially useful for quickly finding highly specific antibodies— for example, the kind you need to develop a rapid at-home test for an emerging disease. Now, no matter which of these three technologies is used to discover antibodies, the work usually doesn’t stop there. That’s because the affinities of naturally-occuring a ntibodies are typically kind of weak— even for ones we consider to be “good”.

Luckily, affinity can be improved. Once a candidate antibody has been found, scientists make tweaks to its sequence. These mutated antibodies go through the phage display process to find the ones with the highest affinity possible.

Then /those/ get tweaked further to try to increase their affinity even more. And it’s mutate, rinse, repeat until you have the best possible one. All of these technological developments have contributed to the soaring popularity of monoclonal antibody treatments.

In fact, in 2018, seven of the top ten best selling drugs were monoclonal antibodies! We’re talking more than 122 /billion/ dollars in sales. But science is always trying to make drugs /better/, and antibodies are no exception. ---outro, supercut---- But here’s Michael with more on that. --outro, dose--- If you want to hear more about the incredible /future/ of antibody technologies... well, the bad news is, there wasn’t enough time for that in /this/ episode.

But the /good/ news is we’ll talk all about it in /the next/ episode! You see, this is part two of our three-part miniseries on antibodies. The link to part 1 is in the description, and you can come back tomorrow for the stunning conclusion! [ outro ].