0
$\begingroup$

Humans and most other mammals produce antibodies consisting of two heavy chains, each linked to a light chain. Both heavy and light chain contribute to the variable region, and thus the antigen specificity of the antibody.

In contrast, cartilaginous fish and camelids have been found to produce heavy-chain-only antibodies, and thanks to their small size and ease of synthesis, camelid antibodies (nanobodies) are predicted to revolutionize antibody therapeutics.

This makes me wonder: why is this not possible with human (genetically engineered) antibodies? Apart from the fact that removing the light chain would alter antigen specificity, what hinders a heavy-chain-only human antibody from being functional? What is so fundamentally different between the camelids heavy chain (and their variable region) and the human equivalent?

Improve this question
$\endgroup$
3
  • 1
    $\begingroup$ It is possible with genetically engineered human antibodies. scAbs and related scFvs (single-chain fragment, variable), which are even smaller, have been around for at least a couple of decades. $\endgroup$
    – MattDMo
    Commented May 28, 2021 at 17:16
  • $\begingroup$ This was the kind of answer I was looking for. I realize my question doesn't reflect that. Thanks! $\endgroup$
    – gaspanic
    Commented Jun 5, 2021 at 16:16
  • $\begingroup$ In case someone else finds this: nature.com/articles/d41586-021-01721-5 $\endgroup$
    – gaspanic
    Commented Jul 6, 2021 at 18:46

1 Answer 1

Reset to default
3
$\begingroup$

I suspect it has to do with the fact that since the camelid scAbs are expressed in vivo, they undergo the normal recombination and affinity maturation process there as individual variable regions. Thus, one can easily isolate high-affinity scAb mRNAs from the blood of a suitably-immunized camelid and proceed with cloning and production.

Human heavy chains undergo affinity selection while paired with light chains and so in vivo processes wouldn't work to generate heavy chains that on their own bind well to the given antigen. I suppose one might generate a display library with only heavy chain genes, but at a typical library complexity of 10^7 you wouldn't be able to cover as much of the "conformation space" as with an in vivo single chain affinity maturation process.

PS - the bit about "revolutionizing antibody therapeutics" seems like marketing hype for a 20+ year old idea.

Improve this answer
$\endgroup$
1
  • $\begingroup$ Thanks. I guess I assumed that in vitro selection would be relatively straightforward with today's technology. But perhaps you're right about the library complexity not being large enough. And yeah, "revolutionizing" might be an exaggeration, but camelid antibody keep popping up every so often, so I really thought it was a newer discovery than 20+. $\endgroup$
    – gaspanic
    Commented May 27, 2021 at 19:34

You must log in to answer this question.

Not the answer you're looking for? Browse other questions tagged .