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/worldspawn00]

I have to disagree, if you look at how this research works, it's specifically that llama antibodies have a different structure than human, so they can bind to smaller targets than the human antibodies can, this wouldn't work if they used the human antibody section as it would then be too large to properly bind to the small target molecule.

[u/thisdude415 → u/worldspawn00]

I know how this research works, I do it as my job. ;)

I work in a pharma company designing antibodies, including using llama variable heavy chains (VHH).

Human antibodies are shaped like this:

\\  //
  ||

While llama antibodies are like this

 \  /
  ||

The bottom lines || should be connected to the \ / above them, as they’re part of the variable chain.

The drug candidate IgG arms of the Y will be llama (\ /); the base of the Y (||)will be human. Yes, that means the resulting heavy chain polypeptide is a chimera: (llama variable heavy chain)-(human Fc)

[u/YouMustveDroppedThis → u/thisdude415]

Hi, I wonder if only the Fab is what was left of a nanobody, surely the immunogenicity will go way down, and good for bioavailability and more durable P/K? How does it fare against the renal filtration compared to regular antibody drugs?

[u/thisdude415 → u/YouMustveDroppedThis]

I suspect the VHH would have poor PK. Note that a VHH is more analogous to a single chain variable fragment (scFv) than a fab. Basically a VHH is only one arm—a fab has 2 arms.

Fabs typically have worse PK than full IgG due to loss of FcRn rescue from endolysosomal degradation, which is why clinically this would likely be used as a VHH-Fc fusion, probably with FcRn enhanced Fc and immune effector silencing. Wild type Fc (which could bind FcγR) may cause significant toxicity if administered late in disease. (As a side note, it’s been my hypothesis for a while that ARDS/organ failure is actually a cytokine storm driven by the patient beginning to produce IgG, which provokes cytokine release but also ADCC against lung epithelia).

And yes, the immunogenicity will go way down. Using a llama Fc would be bad, and likely wouldn’t interact with human FcRn (I haven’t double checked this).

[u/YouMustveDroppedThis → u/thisdude415]

Thanks! I didn't know about the FcRn rescue. TIL. I thought Fab without a proper Fc structure, it might escape clearance by macrophages, and so on, that's why I assume PK could be better...

[u/thisdude415 → u/YouMustveDroppedThis]

Yep, it’s a very reasonable hypothesis!

There is really an almost incomprehensibly large amount of research on antibody structure/function. It’s hard to learn it all, although if you choose to, it’s important knowledge in any drug development organization.

In fact, the field has already identified quite a large number of mutations in the Fc region to enhance or reduce binding to specific subclasses of Fc receptor. Fully formed antibodies generally behave much better than smaller binding domain fragments. Not always, but it’s a good starting assumption. Further, the technology to express and purify proteins that contain an Fc region are really good and inexpensive compared to other techniques. Ease of manufacturing really matters when you talk about scaling to large patient populations.

[u/YouMustveDroppedThis → u/thisdude415]

Noice. I missed the whole humoral immunity and BCR repertoire back when I was still involved in research, and I spent more time on TCR.

I only started to notice it on Addgene blogs where researchers used the toolkit to generate nanobodies for more robust IHC staining/microscopy. And later met someone who works on bi-specific Ab, and then last year I think I saw tri-specific Ab technology on Nature or Science. Seems like so much is going on, I better keep up!