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      Broadly Neutralizing Antibodies for Influenza: Passive Immunotherapy and Intranasal Vaccination

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          Abstract

          Influenza viruses cause annual epidemics and occasional pandemics. The high diversity of viral envelope proteins permits viruses to escape host immunity. Therefore, the development of a universal vaccine and broadly neutralizing antibodies (bnAbs) is essential for controlling various mutant viruses. Here, we review some potentially valuable bnAbs for influenza; one is a novel passive immunotherapy using a variable domain of heavy chain-only antibody (V HH), and the other is polymeric immunoglobulin A (pIgA) induced by intranasal vaccination. Recently, it was reported that a tetravalent multidomain antibody (MDAb) was developed by genetic fusion of four V HHs, which are bnAbs against the influenza A or B viruses. The transfer of a gene encoding the MDAb–Fc fusion protein provided cross-protection against both influenza A and B viruses in vivo. An intranasal universal influenza vaccine, which can induce neutralizing pIgAs in the upper respiratory tract, is currently undergoing clinical studies. A recent study has revealed that tetrameric IgAs formed in nasal mucosa are more broadly protective against influenza than the monomeric and dimeric forms. These broadly neutralizing antibodies have high potential to control the currently circulating influenza virus.

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          Most cited references115

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          Development of therapeutic antibodies for the treatment of diseases

          It has been more than three decades since the first monoclonal antibody was approved by the United States Food and Drug Administration (US FDA) in 1986, and during this time, antibody engineering has dramatically evolved. Current antibody drugs have increasingly fewer adverse effects due to their high specificity. As a result, therapeutic antibodies have become the predominant class of new drugs developed in recent years. Over the past five years, antibodies have become the best-selling drugs in the pharmaceutical market, and in 2018, eight of the top ten bestselling drugs worldwide were biologics. The global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion in 2018 and is expected to generate revenue of $150 billion by the end of 2019 and $300 billion by 2025. Thus, the market for therapeutic antibody drugs has experienced explosive growth as new drugs have been approved for treating various human diseases, including many cancers, autoimmune, metabolic and infectious diseases. As of December 2019, 79 therapeutic mAbs have been approved by the US FDA, but there is still significant growth potential. This review summarizes the latest market trends and outlines the preeminent antibody engineering technologies used in the development of therapeutic antibody drugs, such as humanization of monoclonal antibodies, phage display, the human antibody mouse, single B cell antibody technology, and affinity maturation. Finally, future applications and perspectives are also discussed.
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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

                Journal
                Vaccines (Basel)
                Vaccines (Basel)
                vaccines
                Vaccines
                MDPI
                2076-393X
                29 July 2020
                September 2020
                : 8
                : 3
                : 424
                Affiliations
                [1 ]Department of Microbiology and Immunology, School of Medicine, Aichi Medical University, Aichi 480-1195, Japan; mrityunbio@ 123456gmail.com (M.B.); sachiko@ 123456aichi-med-u.ac.jp (S.A.-T.)
                [2 ]Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585, Japan; chibaj@ 123456rs.noda.tus.ac.jp
                Author notes
                [* ]Correspondence: yamazaki13@ 123456aichi-med-u.ac.jp ; Tel.: +81-56-162-3311
                Author information
                https://orcid.org/0000-0002-7798-914X
                https://orcid.org/0000-0002-2645-6490
                https://orcid.org/0000-0003-4890-3172
                Article
                vaccines-08-00424
                10.3390/vaccines8030424
                7565570
                32751206
                838374f2-0754-4644-ae19-b2fbae292c11
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 08 June 2020
                : 27 July 2020
                Categories
                Review

                cross protection,influenza virus,broadly neutralizing mab (bnab),camelid variable domain of heavy chain only antibody (vhh),multidomain antibody (mdab),passive immunization,intranasal vaccination,polymeric iga (piga)

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