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Single-domain antibodies (or nanobodies) derived from camelid heavy-chain antibodies are called VHH antibodies, where VHH stands for "variable heavy domain of heavy chain". I assume the reason for this name is that the variable domain in the heavy-chain camelid antibody is heavier than other domains. However, I haven't been able to find the weight of each domain in the camelid antibody in order to verify my assumption.

Why are single-domain antibodies derived from camelids called "variable heavy domain of heavy chain"?

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    $\begingroup$ Do you know how "normal" antibodies are composed? $\endgroup$
    – Chris
    Dec 21, 2023 at 13:43
  • $\begingroup$ @Chris thank you for your reply. I am familiar with how normal antibodies are composed but I am not an expert in immunology. Normal antibodies have two heavy chains and two light chains, whereas camelids also possess antibodies with two heavy chains. The VH domain of the heavy chains of normal antibodies is somewhat equivalent to the VHH of the chains of a camelid antibody. I don't understand where the second "H" in VHH comes from, and I was wondering if it comes from the fact that the VHH domain is bigger/heavier than other domains in the chains of camelid antibodies. Thanks! $\endgroup$
    – mgarort
    Dec 21, 2023 at 23:47
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    $\begingroup$ Apologies. Quite frequently computing scientists enter bioinformatics without realizing the need to acquire the background molecular biology. Clearly this is not your situation. I was misled by your suggestion of the VHH domain being "heavier", which doesn't make sense to me. However I agree the additional H in the nomenclature is strange. I'll see if I can track it down. $\endgroup$
    – David
    Dec 22, 2023 at 9:30
  • $\begingroup$ No problem @David, I could have made my question less ambiguous to reduce confusion. Thanks a lot! $\endgroup$
    – mgarort
    Dec 22, 2023 at 11:23

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First, the definition of VHH (and VH) from the article by S Muyldermans — “Nanobodies: Natural Single-Domain Antibodies” in Annu. Rev. Biochem. 2013. 82:775–97.

VHH: antigen-binding variable domain of the H chain of heavy-chain antibodies

VH: the variable domain of the heavy chain of immunoglobulins

So the poster’s definition is incorrect — the term VHH refers to a single domain of the antibody, not the (single-domain) antibody itself.

Why use this acronym, rather than VH, which seems equally applicable? The key point, of which I admit I was not previously aware, is that camels possess both ‘normal’ antibodies composed of heavy and light chains, as well as these special ones with only heavy chains. This is shown in the diagram below, adapted from the original Nature paper describing these antibodies. It actually uses VH in both cases:
Camelid Abs compared
So one can imagine that the term VHH was introduced for convenience when talking about the variable heavy domain of both camelid types. (I haven’t searched for the original myself.) This also emphasizes the point that (presumably) emerged later, that the VH region of the two types of camelid antibody had different genetic origins (IGHV3 and IGHV3H) shown in the diagram below, taken from the Muyldermans review.
camelid VH genes

In conclusion, the poster’s assumption was incorrect: the additional H stands for “(of) Heavy-chain antibody”.

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