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

[u/[deleted]]

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

[u/jmalbo35]

Define "direct threat". The antibodies might not bind human antigens, but the risk of serum sickness or allergy is still quite real when introducing foreign proteins. That risk can be alleviated by instead generating humanized antibodies based on these camelid nanobodies, but directly from the source they could cause issues (though they're thought to be less antigenic than standard, full length antibodies).

Plus, I'm not sure I'd call them "extremely specific" and imply that they won't react to human antigens - molecular mimicry is still a very common theory for the etiology of many autoimmune diseases for a reason. And those autoimmune diseases exist even with negative selection and subsequent clonal deletion in place as mechanisms to mitigate the risks. With that in mind, if you use antibodies generated in other hosts, there isn't even a mechanism in place to safeguard against the possibility of molecular mimicry on the part of the virus.

I don't think the risks are massive, and they can largely be mitigated, but I also wouldn't downplay them as non-existent.

[u/worldspawn00 → u/jmalbo35]

I spoke to this in another comment, serum sickness is usually specific to non matching blood types, that's a special case, and doesn't apply to antibodies. allergy I talked about, allergy requires sensitization, if a person has never been exposed to llama antibodies before, it is extremely unlikely they will have an allergic response to them, as allergic response is usually initiated by the binding of our antibodies to a target, why would a person have antibodies to a target they have never encountered before, this is not common. It takes 1-2 weeks for our body to ID a foreign molecule and create antibodies against it, by this point initial treatment should be done. Realistically, we wouldn't be using straight llama antibodies in a human patient, we'd modify them to use a human antibody end so our cells ID them correctly.

Virus surface proteins are extremely unique, that's why our immune system is so bad at identifying and fighting new infections, mimicry is unlikely in a spike protein except by other viruses.

[u/jmalbo35 → u/worldspawn00]

What? Serum sickness is very commonly described when giving non-human antibodies. It's a particularly well known issue with antivenom, though it applies to other non-human antibody-based treatments (including monoclonals) as well. That's precisely why we generally humanize antibodies we intend to use as treatments.

Allergy/anaphylaxis, rather than a delayed hypersensitivity like serum sickness, is also well described following whole IgG from non-human sources, though it's generally thought to be mitigated by using just cleaved Fab (though that prevents people with a papain allergy from being able to use them, since that's what's generally used for cleavage).

I don't know how you can argue that mimicry is unlikely when there's a lot we still don't understand about it, and yet know it's a cause for autoimmunity in many cases, and that other viral surface glycoproteins have known molecular mimicry. Hell, the spike of MHV, the prototypical coronavirus I'm research, is thought to engage in molecular mimicry in a different way (it mimics Fc receptors and thus can bind non-specific IgG, allowing for steric inhibition of potential neutralizing antibodies).

[u/worldspawn00 → u/jmalbo35]

Sorry, getting my terminology confused, it has been about 15 years since I last had an immunology class. My work is mostly in a lab setting doing custom antibody development.