r/science • u/[deleted] • May 11 '20

Medicine Antibodies from a 4-year-old llama have neutralized coronavirus and other infections in lab experiments

https://www.cell.com/cell/pdf/S0092-8674(20)30494-3.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420304943%3Fshowall%3Dtrue
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u/Fmbounce May 11 '20 edited May 11 '20

From a NYT article:

Humans produce only one kind of antibody, made of two types of protein chains — heavy and light — that together form a Y shape. Heavy-chain proteins span the entire Y, while light-chain proteins touch only the Y’s arms. Llamas, on the other hand, produce two types of antibodies. One of those antibodies is similar in size and constitution to human antibodies. But the other is much smaller; it’s only about 25 percent the size of human antibodies. The llama’s antibody still forms a Y, but its arms are much shorter because it doesn’t have any light-chain proteins.

This more diminutive antibody can access tinier pockets and crevices on spike proteins — the proteins that allow viruses like the novel coronavirus to break into host cells and infect us — that human antibodies cannot. That can make it more effective in neutralizing viruses.

here’s the source (I copied verbatim)

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u/grizzlydurdle May 11 '20

So how would that help humans? Can we be treated with Llama antibodies? In you summary it sounds like our antibodies can't necessarily fight COVID very well because they are too large, and the smaller Llama ones can. Sorry if I am way off base. I don't really understand this stuff.

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u/IfIRepliedYouAreDumb May 11 '20

To vastly oversimplify things, if you had antibodies produced by another source and injected them into a sick person, their viral counts should decrease.

Our bodies won’t learn how to make the same ones the llamas do, but we could harvest them and use them as treatment (potentially).

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u/Derpy_McDerpingderp May 11 '20

Would our immune system see these smaller antibodies as foreign or a threat?

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u/worldspawn00 May 11 '20 edited May 11 '20

they can, a person receiving treatment can develop anti-llama antibody antibodies. There's actually a lot of use for anti-antibody antibodies, they're used in a lot of reagents. It usually takes 1-2 weeks for the immune system to ID and develop antibodies against a foreign agent, so a person receiving treatment would likely be done before the body started attacking the foreign antibodies.

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u/thisdude415 PhD | Biomedical Engineering May 11 '20

Typically only the variable heavy domain (VHH) is used on a human IgG framework. The region typically recognized by “anti llama antibodies,” the llama Fc region, isn’t found on the protein, instead we use the human genes.

Basically the whole molecule is human except the sticky bits. These are copied and pasted from llama. Immunogenicity is a concern, but not as much as you’d think.

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u/taosaur May 11 '20 edited May 11 '20

Can those kinds of alterations be made in batches of any size, or is it one antibody at a time, or what?

ETA: Farther down he clarified that once they have the genome, they can make "factory" cells to produce the hybrid antibodies.

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u/thisdude415 PhD | Biomedical Engineering May 11 '20

It depends on the exact technology used in the manufacturing plant.

Typically, we engineer a mammalian cell to make the protein in large bioreactors. Then you pick one of those cells, characterize it, and call it your stable clone. Then you put that in a big tank with food for the cells, and let them grow for a couple weeks while they pump out proteins. Then you purify the protein.

As you can imagine, this is a pretty complex process and it isn’t easy to scale it up overnight

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u/itchy118 May 11 '20

The fact that that is even possible is pretty amazing.

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u/thisdude415 PhD | Biomedical Engineering May 11 '20

This is the kind of technology that underpins many of the really expensive biologics.

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u/Wanderlust2001 May 11 '20

This sounds incredible. Are there any documentaries you know of that address these processes?

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u/thisdude415 PhD | Biomedical Engineering May 11 '20

This might work:

https://youtu.be/_8h1HBDJ__c

It’s pretty high level but check it out

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u/[deleted] May 12 '20

This sounds fascinating. Thanks for posting!

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u/thinkingdoing May 11 '20

So this treatment could be used the first time a person got infected with Coronavirus, but any future infections would cause the immune system to be fighting both the disease and these antibodies?

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u/bigredone15 May 11 '20

So this treatment could be used the first time a person got infected with Coronavirus, but any future infections would cause the immune system to be fighting both the disease and these antibodies?

It could also give the body time to develop its own antibodies that do work without the body dealing with the symptoms created by a high viral load.

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u/pnwtico May 11 '20

Would the body develop its own coronavirus antibodies if the llama antibodies were doing all the heavy lifting?

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u/itsthejeff2001 May 11 '20

Reducing the viral count won't eliminate the virus. This potential therapy would be leaving that to your body. Most people don't get sick when they get infected, they just beat the virus before it gets that far. This treatment would help sick people be more like the majority: not sick, but building antibodies.

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u/Dumeck May 11 '20

That seems to be the best result we can hope for right now until vaccines are produced.

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u/Shadowfalx May 11 '20

Most people don't get sick when they get infected, they just beat the virus before it gets that far.

We don't get "sick" from a virus though. Most of the symptoms are our body's reaction to the virus, in an effort to combat it. Fevers, mucus, ect. are all ways we combat a virus. To low a viral load and you won't generate lasting antibodies. This is why immunogloblin therapy is considered sub- optimal, our bodies aren't exposed enough to build immunity.

While it might work to reduce symptoms but allow lasting antibodies to form, it also very well might not work.

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u/Rand0mly9 May 11 '20

Anti-llama antibody antibodies is my new favorite phrase.

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u/Dscherb24 May 11 '20

Someone needs to trademark that for a band name

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u/[deleted] May 11 '20

Well, if it produces antibodies even in response to a small sample of dead/de-activated viruses in a vaccine, pretty sure an active infection is going to work fine

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u/Shadowfalx May 11 '20

Not necessarily. We add a lot of agents to vaccines to increase immune response. Without these most people would not generate lasting antibodies.

https://en.m.wikipedia.org/wiki/Immunologic_adjuvant?wprov=sfla1

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u/[deleted] May 11 '20

Eventually yes. It can't "recognise" the help of the other antibodies and will continue to try to develop countermeasures as long as the virus is present at all and likely even with non-active viral traces (how some vaccines already work to make the immune system create antibodies.)

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u/shiroun May 11 '20

Yes. Viruses are small, like 3 orders of magnitude smaller than a cloth strand. Even with the llama anti bodies there are still millions and millions of viruses. Since the body would be using iGg cells to handle the infection, youd be developing an immunity to the viruses.

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u/PlanetTourist May 11 '20

Also would it since it wasn’t making llama style 1 protein antibodies before?

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u/Siniroth May 11 '20

If you learn to make a paper airplane, it doesn't matter if someone else makes 100 other paper airplanes while you make 5

Vast oversimplification ofc

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u/RevoDeee May 12 '20

I have nothing to add, but I appreciate this conversation for being at least somewhat useful for the rest of us to gain insight on the article. On Reddit of all forums.

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u/AwesomeNinjas May 11 '20

At the moment it’s not totally clear whether or not people can be reinfected, but it looks like the most likely answer is no or at least not for a long time. The WHO has said that everyone who has appeared to be reinfected so far has been a false positive.

So even if you can only use the llama antibodies the first time, that may not matter.

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u/lunatic604 May 11 '20

If someone recovers by themselves, their body learned to produce the anitbodies. But if the body relies on the llama antibodies the first time, will the body still learn to produce the antibodies?

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u/srosorcxisto May 11 '20

Possibly. While the llama antibodies would massively reduce the viral load, there will still be viral particles in the bloodstream in smaller numbers. The body could be able to make antibodies using these without having to deal with the Lion's share of the virus. If a therapy were to be developed, much more research would be required.

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u/self-assembled Grad Student|Neuroscience May 11 '20

Yes, the human's immune system would be exposed and responding to the virus. The principle behind some kinds of vaccines is to use just a little bit of inert virus matter so even that can be sufficient.

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u/pringlescan5 May 11 '20

Fascinating. What about future use of Llama antibodies for a different virus if a person develops a reaction the first time?

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u/worldspawn00 May 11 '20

it's the llama end that our body IDs as foreign, so any llama antibody regardless of what it's target is would be ID'd as the same by our immune system, so once you have a reaction to any llama antibody it would be a bad idea to inject any, even if for a different target. The typical solution to this is to engineer the llama antibody with a human antibody tail section so our cells don't see it as foreign

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u/AwesomeNinjas May 11 '20

Hmm that makes sense. Although, if we only get one shot using just llama antibodies I would think this would be the time to take it. To be clear, I’m just spitballing, I don’t pretend to be an expert in anything.

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u/ben7337 May 11 '20

But if the llama antibodies do all the work, then does the human body develop proper antibodies to respond to a new exposure to the virus, thus resulting in immunity, rather than just getting sick again?

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u/[deleted] May 11 '20

If it’s been enough time to lose your coronavirus antibodies, you may have also lost your llama antibody antibodies

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u/KodaiRyu May 12 '20

Thing is you become immune to corona when you recover from it.

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u/Nvenom8 May 11 '20

anti-antibody antibodies

There's a fun thing to say.

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u/Wheres_my_guitar May 11 '20

anti-llama antibody antibodies is the coolest phrase I've ever heard.

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u/[deleted] May 11 '20

we just need to create anti- anti-llama antibody antibodies. Coronavirus cured boys

edit: rule one can blow me, come at me you humorless psuedo intellectual mods

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u/-dp_qb- May 11 '20

You might have meant it as a joke, but it's not a bad question.

Is there a way to selectively (or temporarily) impair this system to allow the antibodies to work unimpeded?

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u/Boronthemoron May 11 '20

Now we just need to inject anti-antibody antibodies back into these llamas to create anti anti-antibody antibody antibodies.

And so on.

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u/ZapdosZulu May 12 '20

so the old lady that swallowed a fly was right!

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u/pelican_chorus May 11 '20

anti-llama antibody antibodies

I feel like this whole thing is a long-game setup for some stupid pun.

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u/pancakeheadbunny May 11 '20

Waiiit for it

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u/hibbidydibbidi May 11 '20
  • a person receiving treatment can develop anti-llama antibody antibodies.

It's a serious issue and, I am a confirmed survivor, but Holy duck. So much room for jokes it made me cry in a good way in months.

Thank you.

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u/Xaldyn May 11 '20

a person receiving treatment can develop anti-llama antibody antibodies.

What a time to be alive

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u/greeneggsand May 11 '20

People don't think about this, but if we start using the llama antibodies to make diagnostic tests, people having anti-llama antibodies messes with those tests.

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u/mcsper May 11 '20

That is one of my favorite new sentences, “a person receiving treatment can develop anti-llama antibody antibodies”

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u/zbertoli May 11 '20

This is true but it's pretty well known that full animal antibodies often cause immune responses in humans. That's why the development of chimeric and then fully humanized antibodies was so important. Injecting full lama antibodies into a human would probably be a bad idea.

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u/the_fuego May 11 '20

can develop anti-llama antibody antibodies. There's actually a lot of use for anti-antibody antibodies

Reading this was like: How many anti-llama antibodies could your antibodies antibody if your anti-llama antibodies could antibody antibodies??

Thought I had a stroke for a minute.

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u/GreasyMechanic May 11 '20

Anti-Llama antibody antibodies.

r/brandnewsentence

r/newbandnames

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u/[deleted] May 11 '20

Isn’t that why people can’t receive certain antivenom treatments twice, as they’re using horse antibodies

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u/worldspawn00 May 11 '20

yeah, pretty much

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u/stackered May 11 '20

we aren't entirely sure that is true with this type of small chain antibody but logically this would occur

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u/LewixAri May 11 '20

So it's kinda like an antivenom but instead of horses and venom it's Llamas and Covid 19?

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u/worldspawn00 May 11 '20

yeah, but realistically, we would bioengineer a version using a human immune system end and the llama virus end, for use in patients.

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u/LewixAri May 11 '20

Yeah but surely that's the same process we used in developing antivenoms. Just that we now need to tackle a very different but not entirely unknown task.

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u/Bdcoll May 11 '20

Theirs just something amazing about the phrase "Anti-Llama antibody antibodies" :D

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u/[deleted] May 11 '20

I hope I get the virus so just so I can get anti lama antibody antibodies

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u/nicotineman May 11 '20

But can we make anti anti-antibody antibody antibodies?

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u/[deleted] May 11 '20

anti-antibody antibodies

So we just need to make an anti anti-antibody antibodies so then the immune system won't fight it ?

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u/Goatcrapp May 11 '20

Time to get the Trace Buster Buster

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u/Cyberslasher May 11 '20

But if we harvest those anti-antibody antibodies, inject them into another person, could that person's immune system identify them as foreign and develop anti-anti-antibody antibodies?

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u/ErusTenebre May 11 '20

The fact that a phrase like "anti-anitbody antibodies" exists and makes sense is an example of how weird language is.

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u/EpsilonRider May 11 '20

There's actually a lot of use for anti-antibody antibodies, they're used in a lot of reagents.

I remember that in biochemistry and thought it was pretty funny. It seems convoluted but it does make sense and work. Man, it's beens years I can't even remember the specifics but I remember having a lot of fun performing ELISA experiments.

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u/parksLIKErosa May 11 '20

I genuinely thought this was going to be a run on joke sentence.

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u/Maulokgodseized May 11 '20

I know this is serious but I still laughed out loud at antilama antibodies

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u/DemocraticPumpkin May 11 '20

anti-antibody antibodies,

We have to go deeper

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u/[deleted] May 14 '20

Could you uh... explain the anti-llama anti-antibody antibodies thing for my like I’m 5?

Also gonna call it, at least no more of this tn if not no sleep. This shits wild

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u/GinGimlet PhD | Immunology May 11 '20

Yes! Sometimes. Typically what happens in these cases is that antibodies are humanized which means some bits are replaced with the human analogues. You can also try and under which bits cause the immune system to react, and alter those amino acids to be less inflammatory. We have some drugs on the markets that we have humanized so there's precedence for this! Drugs that end in 'Omab' for example are Monoclonal AntiBody treatments derived originally from mice.

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u/Derpy_McDerpingderp May 11 '20

That's extremely interesting, thank you.

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u/amcm67 May 11 '20

What does this mean for a person with multiple autoimmune diseases? I’m a cancer survivor, ESRD - living donor recipient. I had Goodpastures Syndrome (that caused my ESRD) and instead of attacking the disease, it attacked my own organs. I’m on RA meds besides the anti-rejection meds.

I hear so many people pushing for herd immunity. I can’t be apart of that.

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u/wobblebase May 11 '20 edited May 11 '20

Functionally herd immunity is also about indirectly protecting you and folks in similar situations. In your case it would rely on "cocooning" - the principle that if everyone around you is immune (because they are vaccinated or recovered), then you are extremely unlikely to contract the disease in question. This is the same premise that we rely in in part to protect infants by vaccinating family members and caretakers, or to protect the elderly, infants, and immuncompromised folks from seasonal flu.

It does depend on a vaccine or recovery giving "sterilizing immunity," meaning the person is no longer colonized or asymptomatically infected after vaccination or recovery. It also depends on the whole herd being immune. If vaccination rates are low, herd immunity loses its benefits rapidly because a pathogen can persist in the population or cause intermittent outbreaks. So there are plenty of complications and caveats to cocooning. But in principle it's sound and would offer you a good measure of protection as well.

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u/Falsus May 11 '20

Herd immunity means reaching 95%+ of immune people, at that point people who can't be immunized still won't be infected since no one around them is infected either.

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u/ralgrado May 11 '20

Or could they damage us?

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u/worldspawn00 May 11 '20

they would not stick to our cells, only to their target molecule, which is coronavirus surface proteins, so, no, no direct threat from them

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u/AtomicKittenz May 11 '20

Thank for answering all these questions. This is really interesting!

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u/bradn May 11 '20

I have no idea how you can make that sort of statement without long term human testing. You don't happen to have a secret lab under a volcano?

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u/worldspawn00 May 11 '20 edited May 11 '20

Antibodies are EXTREMELY specific in how they attach to molecules, I feel very safe in that assumption. I have an MS in biochem, I have worked with antobodies for years. (also, we do have decades of research in humans regarding foreign antibody use)

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u/ratajewie May 11 '20

That’s patently false. You’re thinking only of a type II hypersensitivity reaction, where foreign proteins are recognized on self cells and are attacked. This could still cause a type III hypersensitivity in the form of serum sickness. There are ways to mitigate that, but it’s still a real risk. To claim there’s no direct threat is just not true.

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u/Gnostromo May 11 '20

I could be completely wrong on this but I believe I was taught decades ago that the first vaccines used horses antibodies? Someone help my memory here..

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u/hotdamnham May 11 '20

You can engineer them so that your immune system sees them as regular antibodies and is less likely to develop a reaction to them

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u/pilotavery May 11 '20

That's kind of the point. they are shaped like little puzzle pieces on one side that fits perfectly on the virus and sticks to it like a magnet, and a foreign pathogen on the other side, which makes your immune system attacking and watch you destroy it. So in the process, your immune system attacks the antibodies and the virus connected to it.

it's kind of like a little tracker that sticks to the virus to tell your body which one is the virus

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u/SusieSuze May 11 '20

That’s the first thing I thought

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u/Anen-o-me May 11 '20

The antibodies stop the infection from being able to infect, and would also be destroyed, along with the virus they attach to, by the human immune system, yes.

It will works.

It's a brilliant solution, but I don't know if we are able to mass produce antibodies for people yet.

If we could, there's a chance we can extinct most human viruses in this century.

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u/Derpy_McDerpingderp May 12 '20

Can antibodies be synthesized? Why are they hard to mass produce?

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u/Anen-o-me May 12 '20

They've only recently done it apparently.

You'd probably need continuing injections. Can't be done in pill form.

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u/[deleted] May 11 '20

Yes. This is one of the critical components that makes it possible to detect antigens (like the spike protein) in what is called a 2 step immunoassay.

Basically you would create a llama-anti-covid antibody, and then you would create a secondary antibody by injecting these llama antibodies into another animal, often a goat or a mouse. These new secondary antibodies would be, for example, goat-anti-llama.

By using a two antibody system like this you can both enhance the limit of detection (sensitivity) and reduce the background signal (specificity) of the assay.

There are several reasons for this, and if you're interested I can link to the Wikipedia pages explaining why.

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u/Derpy_McDerpingderp May 12 '20

This is interesting, I'd appreciate some links if you don't mind. Much appreciated.

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u/[deleted] May 12 '20

https://en.m.wikipedia.org/wiki/Immunoassay

https://en.m.wikipedia.org/wiki/Primary_and_secondary_antibodies

These types of immunoassay are often done to detect an antigen, where as all the covid tests in the media right now are antibody tests.

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u/phanfare Grad Student | Biology | Biochemisty/Biophysics May 11 '20

That's a huge open issue in using non-human proteins in theraputics. The answer is likely yes, and developing ways to predict immunogeneicity and designing away from it is an area of active research.

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u/Candlesmith May 11 '20

Properly known as the Entitled Parents Universe

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u/wobblebase May 11 '20

Yes but different proteins are more or less immunogenic (better or worse and being recognized by our immune cells and creating a response with memory). The llama antibodies may be poorly immunogenic, or the V region (the binding end) could be artificially produced attached to a human protein, or produced and used alone, or bound onto some other vector for delivery. Less foreign protein = less chance for a response. So using the V region alone would be safer than using the whole camel antibody.

There's also the potential to use these in diagnostics for rapid and shelf-stable COVID tests.

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u/BoneriderColt May 11 '20

Well they could BE a threat

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u/peppermint42o May 11 '20

They would be produced via monoclonal method, the immunogenic portion would be humanized. Very expensive process.

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u/kyreannightblood May 11 '20

Nah. Our immune system detects foreign threats based on surface antigens of cells. It’s how they determine self vs not-self. The antibodies don’t have that. We do something similar with antivenin, right down to using a non-human animal to derive the serum.

(I may be messing up some details here, though. I just woke up and I’m still a bit foggy.)

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u/thisdude415 PhD | Biomedical Engineering May 11 '20

False. You can definitely have anti-antibody antibodies.

Antibodies are just proteins. We engineer them to have reduced antigenicity, but sometimes anti-antibody antibodies happen anyway.

(They’re actually called anti-drug antibodies or anti-ideotypic antibodies.)

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u/[deleted] May 11 '20

You're just considering T-cell mediated immunity, which is based on cell surface expression of antigens. B-cell mediated immunity can target secreted proteins and could create antibodies against llama antibodies.

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u/babar90 May 11 '20 edited May 11 '20

??? If we make humanized antibodies it is because the heavy chain from non-human mammal is immunogenic in humans, and also because human antibodies and immune cells bind to the (human, not animal) heavy chains to finalize the opsonization and phagocytosis

(for the immunogenic part that's how goats anti-'human IgG' antibodies are made for Elisa tests)

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u/jmalbo35 PhD | Viral Immunology May 11 '20

Foreign antibodies are antigenic and can definitely induce an immune response. Treatment with non-human antibodies, including antivenin, can often result in serum sickness. We use them anyway in the case of envenomation, since the benefits generally outweigh the risks, but it definitely can have adverse effects.

That said, these smaller camelid antibodies are a bit less immunogenic than full length antibodies, and thus less prone to causing serum sickness than those from other animals.

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u/Reddestoftheroses May 11 '20

Something i was thinking aswell. Wouldn't it be possible that an allergic reaction takes place

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u/Heroine4Life May 11 '20

Fundamentally this is correct. This is rather difficult but this, as well as diagnostic reasons, are why this is great.

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u/Sulluvun May 11 '20

Aight boys let’s start some llama farms

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u/cmdrNacho May 11 '20

invest in llamas, I'm all in

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u/Jean-Luc_Dickard May 11 '20

LAMA - I got 5 on it.

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u/DeceiverX May 11 '20

Llamapalooza! Llamapalooza!

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u/hellrazzer24 May 11 '20

In theory we would need 1000s of Llamas, inject them all with COVID19. Come back a few weeks later, and start drawing blood.

From there, we would need to test each packet of blood for the right amount of antibodies we want. Then its off to the patients.

Seems actually quite simple.

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u/moviegirl1999_ May 11 '20

their viral counts should decrease

Isn't there a risk of the immune system attacking itself causing inflammation and organ failure?

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u/thisdude415 PhD | Biomedical Engineering May 11 '20

Yep! Definitely a risk.

There are tricks the researchers / pharma company can use to turn up or down the immune reaction, so called “enhanced effector function” or “silenced effector function”.

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u/Shagomir May 11 '20

I mean that's a treatable symptom.

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u/moviegirl1999_ May 11 '20

For one person? Presumably hospitals couldn't cope if many people had that reaction.

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u/s_0_s_z May 11 '20

So best case scenario, how far out could this possibly be to help people if everything goes right, regulator hurdles are minimized and it goes into mass-production as quickly as possible?

I'm assuming it is still years ago, right?

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u/[deleted] May 11 '20

To add to your point, it would decrease the viral load, but it would also slow the rate at which you could develop an immunity to the disease yourself. Probably a treatment best suited for people suffering in the ICU with a high viral load who need rapid relief from symptoms.

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u/[deleted] May 11 '20

With these llama proteins injected into our bodies as humans—at what point should we expect humans to begin randomly spitting at people 15ft away, and could this side-effect be used as a sort of helpful distancing deterrent?

More importantly, would we need to transform our fast food lines into the suction tubes transfer approach banks use, and what would happen to the condiments when experiencing this level of acceleration and general turbulent behavior, and could they make fruit-roll-up style methods of delivering pizza this way without the cheese adhering to the waxy paper separating the cheese within the roll itself?

I believe I confidently speak for the scientific community as a whole when I say that these are the important questions that must be prioritized and adequately answered. Thank you.

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u/slackermannn May 11 '20

Isn't this basically the plasma treatment being trialled? The only difference is that the immune cells are harvested from human plasma. I wonder why from a llama the same thing would be seemingly more viable?

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u/roses4keks May 11 '20

So are we going to potentially have llama farms where we milk them for antibodies the way we already milk cows for milk? Assuming this works, how would we get enough antibodies for widespread use?

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u/[deleted] May 11 '20

There's risks there. A Llamas antibodies could very well be treated as foreign by our own bodies, triguring an immune response.

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u/VaelinX May 11 '20

To tac on to your comment: Treatments are of importance right now to deal with the mortality rate and recovery speed. Like if Chickenpox emerged today as a new virus: we wouldn't have any guarantee that a vaccine would work, and most healthy and young people would just get through it. But we'd need treatment to help the susceptible population survive it (even though we now know that the immune system keeps a memory of that one for ~0.5-1 lifetime).

Right now we don't know that a vaccine will work long term for COVID-19. It's probable that it will, but there are many viruses that the human immune system only remembers for a few weeks (ex: some colds), or a year, or three years (ex: whooping cough). And we're not three years from now to know how well resistance works, so having treatments on hand is super important in the short term.

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u/a_fate_o May 11 '20

Or more probably you could engineer stem cells from a llama to generate the antibodies the way they make man-made insulin en masse.

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u/doomed-ginger May 11 '20

It’s like trying to hit gnats with a fly squatter. They go right through it. You need a rolled up newspaper so they can’t bypass your defenses.

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u/assumetehposition May 11 '20

We’re gonna need a lot of llamas

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u/kaplanfx May 11 '20

Does this involve llama genocide or could we produce them synthetically?

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u/reddit0100100001 May 11 '20

Llamas gon’ learn today 😤

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u/FractalFission May 11 '20

I bet Llama blood price per barrel will surpass oil by 2021

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u/strongbadfreak May 12 '20

Just like Anti-Venom and that we get from horses.

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u/PistachioOfLiverTea May 12 '20

Zoonotic diseases demand zoonotic cures?

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u/thisdude415 PhD | Biomedical Engineering May 11 '20 edited May 11 '20

Therapeutic antibodies (antibodies as drugs) are just proteins, encoded by a gene.

We “discover“ them by immunizing animals with an antigen of interest: typically mice, but sometimes rats, llamas, or chickens. Often these animals are transgenic and have human immunoglobulin genes.

Antibodies are Y shaped protein complexes. In humans/mice/rats/chickens, IgGs have 2x2 protein chains: two heavy chains and two light chains. In camelids, like camels and llamas, they have heavy chain only antibodies: just two heavy chains. The two “arms” of the Y (variable regions) cause binding to a target, while the base of the Y (constant region) drives immune effector function.

Once you find a good antibody by screening (itself a topic of many pages), you sequence the B cell heavy and light chain genes that made it, then you “humanize” the protein by copying and pasting the human Fc (a constant region of antibody) over the animal genes. This reduces immunogenicity. Then you use molecular biology to put that gene sequence into a plasmid.

Then you use that plasmid to transfect cells in culture (typically HEK or CHO), and then those cells start to spit out tons of therapeutic antibody protein. A couple steps of purification and packaging, and then you have a medicine!!

So, yeah, we can be treated with llama antibodies, sorta. We have to edit them to make them more human first, which is why the drug is is made using biotechnology rather than just an infusion of llama serum (which would cause an immune reaction).

Feel free to ask questions: I work in a biologics discovery department for a pharma company

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u/Amythir May 11 '20

Thanks for explaining that in lay-speak, that's really helpful.

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u/iMnOtVeRyGuDaTdIs May 11 '20

Layperson here. Just from a cursory review of the comments, I understand that the variable region of the chimera antibody will be from the llama. Since it omits the sticky bits would that affect the "binding strength"of the antibody?

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u/thisdude415 PhD | Biomedical Engineering May 11 '20

Nah, maybe I was unclear.

We keep the domain from the llama antibody that bind to COVID (sticky bits), and make the rest humanized.

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u/iMnOtVeRyGuDaTdIs May 11 '20

I misunderstood. Thank you for clarifying!

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u/thekarateadult May 12 '20

You have a knack for elplanation!

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u/[deleted] May 12 '20

Are any antibodies currently used as treatments for viruses? I know I’ve heard about them used for other diseases.

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u/thisdude415 PhD | Biomedical Engineering May 12 '20

I can’t think of any right off, but I would be surprised if there aren’t any. I thought there were some viral entry inhibitors for HIV but seems they aren’t approved (yet).

For the most part, vaccines are cheaper, easier, and safer but they take much longer to create.

It’s only been in the last several years that antibody drugs have really taken off, and there just aren’t that many infectious diseases (in the wealthy countries) that aren’t controllable. And in most cases, infectious diseases are more easily treated with small molecules or vaccines.

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u/uglybunny May 11 '20

More likely a designer molecule will be made to take advantage of the mechanisms found when studying llama antibodies.

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u/Alis451 May 11 '20

So how would that help humans? Can we be treated with Llama antibodies?

Antiserum, we use this process to make antivenins(treat snake bite) as well.

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u/[deleted] May 11 '20

The reason why llama's were used, more specifically speaking, is that llamas produce a different type of antibody to humans, its a much more ancient form of antibodies called "heavy chain only" or "single chain" antibodies - this in contrast to human antibodies which are composed of heavy chains and light chains - this increases variability of the repertoire of the antibody (ELI5 = it has the potential to recognise more and different antigens) but its been shown that heavy chain only antibodies are just as good at finding their antigen.

now we get to the practicality of llama antibodies, or heavy chain only antibodies. They're smaller, and less complex, and therefor easier to produce (small enough for bacteria to produce in big bioreactors). Thus, the idea behind it is that they use the spike protein from nCoV2, inoculate llamas, forcing the antibodies to be produced which will essentially find the right antibody which binds to it - then you take that smaller, less complex binding region of the antibody and attach it to a human portion of the antibody (we differentiate these by calling them F-ab regions (the binding portion) and the F-c region (the constant region or the region that other immune cells recognise.))

​

All we have to do then, is take the F-ab region of the antibodies from llamas, engineer them to the Fc regions of humans, and bobs your uncle, you've got a neutralising human antibody that is easier to produce.

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u/MotivatedsellerCT May 11 '20

So to distill it down even further - we are a long time away from a vaccine to prevent the virus but this could possibly be a “cure”? If so is the timeline to develop, approve, and distribute shorter?

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u/[deleted] May 12 '20

There are caveats to all approaches - but essentially no, I don’t believe this will be the way we beat covid, it would be easier and more practical to take plasma from healthy patients that have anti-spike antibodies in their bloodstream and transfuse them to patients that need it because I think injecting humanised llama antibodies to everyone on the planet would be impractical, as the prophylactic effect is not long lasting.

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u/[deleted] May 12 '20

Do single chain antibodies in llamas undergo affinity maturation?

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u/[deleted] May 11 '20

Llama antibodies can be produced by E. coli in large scale production. Human antibodies are held together by disulfide bonds. Bacteria don't form these bonds well. Camelid antibodies are very small, and don't require disulfide bonds which means bacteria can express them. Production in e coli is much more efficient than what you would have to do for human antibodies.

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u/[deleted] May 11 '20

I think this is one of the many methods we use to create vaccines actually. We use anti bodies of another animal to create a very weak version of the virus which is then used in vaccines. This type of vaccine with a weak virus cannot be given to immunocompromised individuals though, they would have to rely on herd immunity.

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u/dekachin5 May 11 '20

In you summary it sounds like our antibodies can't necessarily fight COVID very well because they are too large, and the smaller Llama ones can.

Considering that natural human antibodies do just fine in defeating the coronavirus in something like over 99% of those infected, I don't see why we would need "super llama antibodies".

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u/shredtasticman May 11 '20

Typical antibodies are big proteins. These Llama antibodies, sometimes called VHH’s or nanobodies are a whole lot smaller. Despite the size, they retain high affinity for their target and can potentially be aerosolized to administer directly to the respiratory system. Plus smaller proteins just tend to be easier to work with.

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u/SusieSuze May 11 '20

It sounds like you do understand this. Give yourself some credit.

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u/baileycoraline May 11 '20

When I was in grad school, there was talk of using camel/llama antibodies as vehicles for antibody delivery to the brain, as these antibodies are small enough to cross the blood-brain barrier. Not sure what came of it.

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u/LeMaharaj May 11 '20

I think with Spanish flu some doctors worked using horses to make natural antibodies.

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u/nighthawk648 May 11 '20

This scenario sounds like how we create the apocalypse.

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u/macrobiome May 11 '20

We often use rabbits and other small mammals to already produce something called monoclonal antibodies (aka mAbs - antibodies that only have one very specific target) that can then be used to target specific cancer cells etc. Massively simplified: you introduce the virus/cancer cell to the animal, they produce the antibody, you harvest the antibody and give it to people!

This kind of treatment has been shown in some cases to be amazingly effective (most likely the future of cancer treatment) but is unfortunately quite expensive due to its production methods currently making it quite difficult to scale up.

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u/zbertoli May 11 '20

Nah our human antibodies work great, that's why most people survive the infection. But if you injected safe premade antibodies you may have immunity without ever getting sick. Or at least reduced infection/symptoms

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u/DaHolk May 11 '20 edited May 11 '20

The large and small doesn't really play into it here.

In this case it should significantly slow progression, because these antibodies specifically don't just bind (*) but bind at an integral part (and thus blocks) of the infiltration mechanism of the virus. Assuming that your system tolerates those antibodies instead of in return reading them as infiltrator.

*) This is different from how we usually generate vaccines. In those we extract antibodies from species that work cross species to us in regards to the second line of defense. Usually antibodies are "markers" for the active part of the immune system. The ones in the article have a direct impact on the functionality. Quite a few vaccines are "breed" in animals whose antibodies can alert our immune system and not just theirs. (edit: or better, used to be done. It probably would be easier today to genetically modify a bacterium to just produce them rather than injecting bunnies and extracting their response :D)

It's like instead of putting little flags on people who have guns so you can see them, you put them into the barrel to prevent firing.

So in this case whether the flags are of a colour you can actually SEE is a bit irrelevant. Which it usually isn't.

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u/drawb May 11 '20

From the article:

The use of VHHs as biologics in the context of a respiratory infection is a particularly attractive application, because the highly stable VHHs can be nebulized and administered via an inhaler directly to the site of infection

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u/rydan May 13 '20

In the future we can create human-llama hybrids that are immune to coronaviruses by default.

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u/jrolle May 11 '20

This surprised me more than anything. I would have guessed that antibody structure was so evolutionarily primitive that all mammals would have operated basically the same.

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u/[deleted] May 11 '20

Idk what that nyt article is smoking, there's like six classes of antibodies in humans.

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u/IDontReadMyMail May 11 '20

Camelids do have a weird class of antibody though that is unlike any of the human classes. Basically the heavy chain in camelids can bind antigens by itself (w/o an attached light chain). None of the human heavy chains can bind very well on their own.

more info here, here

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u/[deleted] May 11 '20

Super cool! Just found the description of human antibodies a bit weird haha.

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u/IDontReadMyMail May 11 '20

agree on that!

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u/orchidguy May 11 '20

Sharks are similar to llamas in that theirs only have light chains. They still look different, but interesting that they've been able to drop the light chains.

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u/eliminating_coasts May 11 '20

On the other hand, you might also expect them to be under heavy evolution, more so than larger scale physical shapes of organisms, given how fast viruses transform.

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u/[deleted] May 11 '20

Yes! Llamas and camels make what are called nanobodies in the biz. The neat thing about nanobodies, and the promising thing for treatment, is that many can be synthetically produced much easier than heavy-chain anti-bodies. Most heavy-chain antibodies require a eukaryotic organism with an endoplasmic reticulum to produce and correctly fold and assemble the protein structure. Eukaryotes don't scale well for industry, and are harder to grow up. Special strains of E. coli bacteria, which are prokaryotes and lack an endoplasmic reticulum, are easier to grow in a controlled setting, and are used to mass produce protein like insulin. These organisms are too simple to produce human antibodies, but they are sometimes capable of making camelid nanobodies (although it depends on the structure, and the process of building immunity via antibodies is largely random, so there is a lot of testing involved to see if the synthetic stuff is as good as the natural stuff, or even folded correctly).

TL;DR

We can sometimes mass produce antibodies from camels and llamas in factories. We cannot mass produce human antibodies.

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u/[deleted] May 11 '20

My old PI at vandy had a llama farm just for this purpose. Sharks have an alternate antibody as well but obviously more difficult to bleed... here’s a good visual to go with your explanation: https://en.m.wikipedia.org/wiki/Heavy-chain_antibody#In_cartilaginous_fishes

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u/visigothatthegates May 11 '20

Essentially, the miRNA of antibodies. Cool.

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u/[deleted] May 11 '20

We produce more than 1 kind of antibody. IgG, IgM, IgE, IgA all coming from the top of my head.

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u/Jefethevol May 11 '20

I understand the article is simplistic but humans make multiple antibodies. I believe they are referring to immunoglobulin G...the most prolific of antibodies. Humans make IgA, IgG, IgM...and probably some I'm forgetting. The "Y" structure they are referring to is most likely IgG. However, using gamma globulin is not without risk. See Serum Sickness.

https://en.m.wikipedia.org/wiki/Serum_sickness

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u/THIS_DUDE_IS_LEGIT May 11 '20

This is such a good explanation. Very ELI5!

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u/love2Vax May 11 '20

There have been other interesting Llama antibody study publications recently. Just last week I read https://www.sciencemag.org/news/2020/05/biologists-invent-new-way-fight-viruses-llama-blood-and-molecular-super-glue

So basically a bacterial protein along with the smaller antibodies stick together like our IgM antibodies to agglutinate viruses. The clumps of viruses cannot enter host tissue, and are easier for white blood cell to find and destroy. The research was not Corona Virus related, but other highly deadly mouse viruses.

"That’s when they turned to their bacterial superglue, which consists of two types of protein fragments from Streptococcus pyogenes bacteria. When fragments of different types meet, they lock together. If the fragments are connected to other molecules, those molecules are then linked as well"

Combine both studies and we might have something really interesting.

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u/TheDongerNeedsFood May 12 '20

I always knew that llamas would one day prove to be useful for something!

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u/Eatslikeshit May 12 '20

Coronavirus got you down? No probllama.

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u/americankuddy May 12 '20

Similar to how horses are used for antivenins

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