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      Camelid Single-Domain Antibodies: Historical Perspective and Future Outlook

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          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 V HHs, 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 V HH-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.

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          Most cited references115

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          Continuous cultures of fused cells secreting antibody of predefined specificity.

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            Nanobodies: natural single-domain antibodies.

            Sera of camelids contain both conventional heterotetrameric antibodies and unique functional heavy (H)-chain antibodies (HCAbs). The H chain of these homodimeric antibodies consists of one antigen-binding domain, the VHH, and two constant domains. HCAbs fail to incorporate light (L) chains owing to the deletion of the first constant domain and a reshaped surface at the VHH side, which normally associates with L chains in conventional antibodies. The genetic elements composing HCAbs have been identified, but the in vivo generation of these antibodies from their dedicated genes into antigen-specific and affinity-matured bona fide antibodies remains largely underinvestigated. However, the facile identification of antigen-specific VHHs and their beneficial biochemical and economic properties (size, affinity, specificity, stability, production cost) supported by multiple crystal structures have encouraged antibody engineering of these single-domain antibodies for use as a research tool and in biotechnology and medicine.
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              Naturally occurring antibodies devoid of light chains.

              Random association of VL and VH repertoires contributes considerably to antibody diversity. The diversity and the affinity are then increased by hypermutation in B cells located in germinal centres. Except in the case of 'heavy chain' disease, naturally occurring heavy-chain antibodies have not been described, although antigen binding has been demonstrated for separated heavy chains or cloned VH domains. Here we investigate the presence of considerable amounts of IgG-like material of M(r) 100K in the serum of the camel (Camelus dromedarius). These molecules are composed of heavy-chain dimers and are devoid of light chains, but nevertheless have an extensive antigen-binding repertoire, a finding that calls into question the role of light chains in the camel. Camel heavy-chain IgGs lack CH1, which in one IgG class might be structurally replaced by an extended hinge. Heavy-chain IgGs are a feature of all camelids. These findings open new perspectives in the engineering of antibodies.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/389839
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                20 November 2017
                2017
                : 8
                Affiliations
                [1] 1Human Health Therapeutics Research Centre, National Research Council Canada , Ottawa, ON, Canada
                [2] 2Department of Biology, Carleton University , Ottawa, ON, Canada
                Author notes

                Edited by: Marc H. V. Van Regenmortel, Centre national de la recherche scientifique (CNRS), France

                Reviewed by: Serge Muyldermans, Vrije Universiteit Brussel, Belgium; Etienne Weiss, Ecole Supérieure de Biotechnologie de Strasbourg, France

                *Correspondence: Mehdi Arbabi-Ghahroudi, mehdi.arbabighahroudi@ 123456nrc-cnrc.gc.ca

                This is NRC publication number: 53362.

                Specialty section: This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.01589
                5701970
                026a21dd-c48b-4ec7-a9d6-da8353b8b57f
                Copyright © 2017 Arbabi-Ghahroudi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 102, Pages: 8, Words: 7432
                Funding
                Funded by: National Research Council Canada 10.13039/501100000046
                Categories
                Immunology
                Perspective

                Immunology
                camelid single-domain antibody,heavy chain antibody,vhh,nanobody,antibody engineering,therapeutic antibody

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