Abstract
Tremendous effort has been expended over the past two and a half decades to understand many aspects of camelid heavy chain antibodies, from their biology, evolution, and immunogenetics to their potential applications in various fields of research and medicine. In this article, I present a historical perspective on the development of camelid single-domain antibodies (sdAbs or VHHs, also widely known as nanobodies) since their discovery and discuss the advantages and disadvantages of these unique molecules in various areas of research, industry, and medicine. Commercialization of camelid sdAbs exploded in 2001 with a flurry of patents issued to the Vrije Universiteit Brussel (VUB) and later taken on by the Vlaams Interuniversitair Instituut voor Biotechnologie (VIB) and, after 2002, the VIB-founded spin-off company, Ablynx. While entrepreneurial spirit has certainly catalyzed the exploration of nanobodies as marketable products, IP restrictions may be partially responsible for the relatively long time span between the discovery of these biomolecules and their entry into the pharmaceutical market. It is now anticipated that the first VHH-based antibody drug, Caplacizumab, a bivalent anti-vWF antibody for treating rare blood clotting disorders, may be approved and commercialized in 2018 or shortly thereafter. This elusive first approval, along with the expiry of key patents, may substantially alter the scientific and biomedical landscape surrounding camelid sdAbs and pave the way for their emergence as mainstream biotherapeutics.
Highlights
The canonical view of antibodies as molecules composed of two heavy chains and two light chains was forever changed one day in 1989 following analysis of total and fractionated immunoglobulin G (IgG) molecules in the serum of a dromedary camel in the laboratory of Professor Raymond Hamers at the Vrije Universiteit Brussel (VUB)
The sequencing results showed that nature had designed heavy chain-only antibodies (HCAbs) as an additional arm of the immune systems of camelid ungulates over the course of their evolutionary history. The consensus of these studies suggested camelid HCAbs possessed: (a) no CH1 domain, and a direct connection of the rearranged VHH exon to the hinge region; (b) one of two types of long (IgG2) and short (IgG3) hinge isotypes; (c) specific conserved amino acid substitutions in framework region 2 (FR2), mainly at VH positions that make contact with the VL in classical antibodies, including Kabat positions 37, 44, 45, and 47; and (d) potentially different CDR3 amino acid composition and a broader length distribution for CDR3 compared to the heavy chains of conventional antibodies [1, 16, 17]
The consensus of immunogenetic studies of camelid HCAbs is that repertoire diversification of these molecules may involve (a) a large number of unique VHH gene segments recombining with DH and JH minigenes, possibly with additional nontemplated nucleotide insertions leading to longer CDR3 loops; (b) somatic hypermutation, potentially of extended CDR1 regions compared with conventional antibodies; (c) acquisition of non-canonical cysteine residues in the CDRs and FR2; and
Summary
The canonical view of antibodies as molecules composed of two heavy chains and two light chains was forever changed one day in 1989 following analysis of total and fractionated immunoglobulin G (IgG) molecules in the serum of a dromedary camel in the laboratory of Professor Raymond Hamers at the Vrije Universiteit Brussel (VUB). Further evidence of the unique antigen recognition behavior of VHH domains (including enzyme inhibition) was published over the several years [11, 14, 15], suggesting that VHHs might probe different sets of epitopes on proteins compared with conventional antibodies.
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