Structure and Function of Camelid VHH

The humoral immune response of camels and llama’s is unique in containing two types of IgG antibodies: classical heterotetrameric and homodimeric heavy chain-only antibodies (HCAbs). Remarkably, these heavy chain antibodies are functional in antigen binding and reach high titers and affinities after immunizing a camelid. Antigen recognition by HCAbs is mediated by one single variable domain, referred to as VHH. In comparison to VHs of classical antibodies, VHHs harbor notable sequence and structural adaptations clarifying their solubility and antigen-binding capacity in absence of a VL. The genome of camelids contains a significant set of dedicated IGHGH genes and IGHVH germ line genes with VHH-sequence adaptations. During B cell maturation, one IGHVH germ line gene recombines with one IGHD and one IGHJ mini gene out of a pool, to generate a VHH domain that is eventually rearranged to a dedicated IGHGH gene where the region encoding the first constant domain is removed by splicing, to produce a functional HCAb. Cloning the VHH repertoire of an immunized camelid from which to retrieve antigen-specific VHHs gives access to single-domain, nanometer-sized, antigen binding fragments, known as nanobodies. These are employed as versatile research tools, in numerous diagnostic tests and as therapeutics.