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These days, we’re pretty good at harnessing the power of antibodies for medicines and as molecular tools, but they do have some drawbacks. So, cutting-edge researchers are hoping to develop smaller and more stable alternatives, and they’re willing to try just about anything from chopping antibodies up to creating plastic mimics!

Antibodies Series Part 1: https://youtu.be/nKl5RY1-Vwk
Antibodies Series Part 2: https://youtu.be/pFatmpFqWdo

Hosted by: Michael Aranda

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Sources:
Antibodies as Medicines
https://pubmed.ncbi.nlm.nih.gov/29973504/
https://doi.org/10.2165/00003088-199528020-00004
Antibody Fragments
https://pubmed.ncbi.nlm.nih.gov/20093855/
https://pubmed.ncbi.nlm.nih.gov/31544842/
https://doi.org/10.1155/2012/980250
Mini-Binders
https://doi.org/10.1038/nature23912
https://doi.org/10.1126/science.abd9909
https://doi.org/10.1016/j.tibs.2019.12.008
https://doi/org/10.1126/science.aaz8818
Plastic Antibodies
https://doi.org/10.1021/ja102148f
https://doi.org/10.1016/j.snb.2011.07.039
https://doi.org/10.1038/srep26132
https://doi.org/10.1002/anie.201602076
https://doi.org/10.1002/(SICI)1520-636X(1998)10:3%3C195::AID-CHIR1%3E3.0.CO;2-9

Images:
https://science.sciencemag.org/content/370/6515/426
https://www.istockphoto.com/photo/llama-up-close-gm1209120485-349767631
https://www.istockphoto.com/photo/3d-render-antibodies-identify-and-neutralize-pathogen-virus-over-black-background-gm1222559388-358781728
https://www.istockphoto.com/photo/antibodies-destroy-an-infected-cell-by-a-virus-immun-defense-kill-the-infected-cell-gm1218459794-356049018
https://www.istockphoto.com/photo/young-woman-having-a-nasal-swab-test-gm1266490168-371290691
https://www.istockphoto.com/photo/eerie-light-radiating-from-tip-of-needle-of-medical-syringe-gm1291953530-386917452
[♩INTRO].

Antibodies deserve a ton of credit they’re these sticky little Y-shaped  proteins that our immune systems use to spot and neutralize basically  every kind of threat to us. They’re so useful that, for more than a  century, scientists have been harnessing their powers in medicines and as molecular tools.

And we’ve gotten really good at finding  a great antibody for a given job; making it even better at binding its target,  or antigen; and then mass-producing it. But these monoclonal antibodies  do have some drawbacks. While they’re small compared to  pathogens, they’re still big for proteins.

That makes them pretty fragile  when it comes to high temperatures, which can make shipping and storage tough. Also, they can’t always fit into the  nooks and crannies we want them to. And that’s even if you can even get  them into the body in the first place!

Antibody drugs are typically injected,  so they have to be mixed with liquid. But some antibodies either don’t  dissolve well or will clump up together when they do, which takes injection off the table. All of this is why, as great as  antibodies are, cutting-edge researchers are hoping to develop smaller  and more stable alternatives.

And they’re willing to try just about anything from chopping antibodies up  to creating plastic mimics. When you have something that’s too big, the most obvious solution is to make it smaller. That’s easier said than done, of course.

Luckily, with antibodies, it’s  actually pretty straightforward. The proteins are already kind of  modular, sort of like the IKEA furniture you can piece together to  create your dream bookshelf. And in fact, the immune systems of some  other animals take advantage of this!

Llamas and other camelids naturally  produce smaller antibodies that consist of just one part of what we’d  consider a normal antibody. Those helped scientists realize  they could somewhat pick and choose which pieces of  an antibody to work with. And those choices give them control  over things like how long the designer antibodies stick around inside  you, where they’re effective, and how they interact with their antigens.

For example, antigen-binding fragments, or Fabs, are essentially just one  complete arm of an antibody. These fabulous mini-antibodies  are already being used to diagnose and treat cancer, prevent blood  clots, and treat macular degeneration. Or, you can use the sticky bits all by themselves that’s essentially what  single-chain variable fragments are.

They’re being used in the  development of antitumor drugs, as tracers for identifying and  diagnosing cancers, as antitoxins, and as treatments for inflammatory  diseases like rheumatoid arthritis. With both Fabs and these single-chain  variable fragments, the smaller size allows them to reach locations in the  body that larger antibodies can’t. But without the stabilizing  components of antibodies, they don’t tend to hang around very long.

Plus, on a molecular scale,  they’re still pretty big, and likely to be sensitive to high temperatures. So some scientists are trying to take  this miniaturization idea even further. Researchers at the University of  Washington are hoping to design super mini-proteins that attack and  neutralize pathogens like antibodies do.

These tiny proteins are just as  stable as full-sized proteins. And they actually occur naturally  in humans and other animals. It’s just that, until recently, our  methods of detecting proteins weren’t good at spotting ones this small.

And they are small! Between 40 and 400  times smaller than the average protein. Rather than relying on natural ones, though, the UW researchers are designing their own.

They’re developing machine-learning  algorithms which figure out the smallest possible proteins with the highest  possible stickiness for a given antigen. Then, they build them and test them out. They’ve decided to call  their creations mini-binders.

Because they’re mini. And bind to things. And since these mini-binders are  much smaller than regular antibodies, they have several advantages.

They’re much less fragile and can  withstand higher temperatures, for example. Also, they could be administered  by nose spray instead of injection. And they can be designed to bind a  pathogen in multiple different ways without being too unwieldy, which would make it less likely for a  mutation to render them ineffective.

As a proof of concept, the  team designed some mini-binders to target the flu and SARS-CoV-2 viruses. And the results were promising! Mice who got them were just as  likely to survive their infections as mice that got full-fledged antibodies.

But mini-binders are still in  the early stages of development, which means we don’t yet know if  they would even work in humans. So a lot needs to be done before we  can even consider counting on them as a quick response to emerging pathogens. And there are other ideas  for the future of antibodies… not all of which are biological in nature.

In 2010, scientists in California  successfully made plastic antibodies. They forced synthetic molecular subunits  to grow into long, branching chains around bee venom toxins. Then, they dissolved the actual venom leaving behind plastic polymers  with perfect, toxin-shaped pockets.

And they worked! When they gave these plastic  antibodies to mice who had been exposed to bee venom, about 60% of them lived,  while none of the control group did. What’s great about these plastic  versions is that they’re cheap to make and incredibly stable.

They can just sort of hang out wherever. That means that, in addition to working  inside the body, they could be used in field sensors, point-of-care  diagnostic tests, even deodorants! Pretty much anywhere you might want the  ability to grab a specific molecule.

But the current process for  making them does require A LOT of the target antigen, which could be  difficult to obtain or might get expensive. And the plastic antibodies made so far  aren’t as specific as actual antibodies, nor are they smaller. So, there’s plenty of room for improvement.

But whether we’re talking plastics  or simply smaller proteins, it’s clear that antibody technologies  have come an incredibly long way since the horse-blood treatments  of the 19th and 20th centuries. They’ve helped us treat snake bites,  cancers, inflammatory diseases, blood clots, viruses, and blindness. And they’ve given us a window into our bodies from telling us what we’re sick with  to letting us know if we’re pregnant.

Plus, they’ve become essential  tools in the laboratory, all thanks to their unmatched  ability to stick to specific things. And as researchers develop new kinds of antibodies and antibody-inspired technologies,  the potential applications for them, both in and out of medicine, is  only going to continue to grow. Thanks for watching this episode of SciShow the third and final episode  in our antibodies mini-series!

Missed parts 1 or 2? No worries! The links are in the description.

And here’s a tip: if you click that subscribe  button and ring that notification bell, you’ll get an alert every  time we post a new episode. So you’ll never miss one again! [♩OUTRO].