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      Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus

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          Abstract

          Neutralization of West Nile virus (WNV) in vivo correlates with the development of an antibody response against the viral envelope (E) protein. Using random mutagenesis and yeast surface display, we defined individual contact residues of 14 newly generated monoclonal antibodies against domain III of the WNV E protein. Monoclonal antibodies that strongly neutralized WNV localized to a surface patch on the lateral face of domain III. Convalescent antibodies from individuals who had recovered from WNV infection also detected this epitope. One monoclonal antibody, E16, neutralized 10 different strains in vitro, and showed therapeutic efficacy in mice, even when administered as a single dose 5 d after infection. A humanized version of E16 was generated that retained antigen specificity, avidity and neutralizing activity. In postexposure therapeutic trials in mice, a single dose of humanized E16 protected mice against WNV-induced mortality, and may therefore be a viable treatment option against WNV infection in humans.

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          The online version of this article (doi:10.1038/nm1240) contains supplementary material, which is available to authorized users.

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          Most cited references36

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          Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States.

          In late summer 1999, an outbreak of human encephalitis occurred in the northeastern United States that was concurrent with extensive mortality in crows (Corvus species) as well as the deaths of several exotic birds at a zoological park in the same area. Complete genome sequencing of a flavivirus isolated from the brain of a dead Chilean flamingo (Phoenicopterus chilensis), together with partial sequence analysis of envelope glycoprotein (E-glycoprotein) genes amplified from several other species including mosquitoes and two fatal human cases, revealed that West Nile (WN) virus circulated in natural transmission cycles and was responsible for the human disease. Antigenic mapping with E-glycoprotein-specific monoclonal antibodies and E-glycoprotein phylogenetic analysis confirmed these viruses as WN. This North American WN virus was most closely related to a WN virus isolated from a dead goose in Israel in 1998.
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            Structure of the dengue virus envelope protein after membrane fusion.

            Dengue virus enters a host cell when the viral envelope glycoprotein, E, binds to a receptor and responds by conformational rearrangement to the reduced pH of an endosome. The conformational change induces fusion of viral and host-cell membranes. A three-dimensional structure of the soluble E ectodomain (sE) in its trimeric, postfusion state reveals striking differences from the dimeric, prefusion form. The elongated trimer bears three 'fusion loops' at one end, to insert into the host-cell membrane. Their structure allows us to model directly how these fusion loops interact with a lipid bilayer. The protein folds back on itself, directing its carboxy terminus towards the fusion loops. We propose a fusion mechanism driven by essentially irreversible conformational changes in E and facilitated by fusion-loop insertion into the outer bilayer leaflet. Specific features of the folded-back structure suggest strategies for inhibiting flavivirus entry.
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              Monoclonal antibodies that bind to domain III of dengue virus E glycoprotein are the most efficient blockers of virus adsorption to Vero cells.

              The specific mechanisms by which antibodies neutralize flavivirus infectivity are not completely understood. To study these mechanisms in more detail, we analyzed the ability of a well-defined set of anti-dengue (DEN) virus E-glycoprotein-specific monoclonal antibodies (MAbs) to block virus adsorption to Vero cells. In contrast to previous studies, the binding sites of these MAbs were localized to one of three structural domains (I, II, and III) in the E glycoprotein. The results indicate that most MAbs that neutralize virus infectivity do so, at least in part, by the blocking of virus adsorption. However, MAbs specific for domain III were the strongest blockers of virus adsorption. These results extend our understanding of the structure-function relationships in the E glycoprotein of DEN virus and provide the first direct evidence that domain III encodes the primary flavivirus receptor-binding motif.
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                Author and article information

                Contributors
                diamond@borcim.wustl.edu
                Journal
                Nat Med
                Nat. Med
                Nature Medicine
                Nature Publishing Group US (New York )
                1078-8956
                1546-170X
                24 April 2005
                2005
                : 11
                : 5
                : 522-530
                Affiliations
                [1 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Department of Molecular Microbiology, , Washington University School of Medicine, ; 660 South Euclid Avenue, Box 8051, St. Louis, 63110 Missouri USA
                [2 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Department of Medicine, , Washington University School of Medicine, ; 660 South Euclid Avenue, Box 8051, St. Louis, 63110 Missouri USA
                [3 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Department of Pathology & Immunology, , Washington University School of Medicine, ; 660 South Euclid Avenue, Box 8051, St. Louis, 63110 Missouri USA
                [4 ]GRID grid.421076.6, ISNI 0000 0004 0432 6278, MacroGenics, ; 1500 East Guide Drive, Rockville, 20850 Maryland USA
                [5 ]GRID grid.465543.5, ISNI 0000 0004 0435 9002, New York State Department of Health, , Wadsworth Center, ; 5668 State Farm Road, Slingerlands, 12159 New York USA
                Article
                BFnm1240
                10.1038/nm1240
                1458527
                15852016
                c8a0a2fb-a3d1-4fac-9ccd-81bfc8b6bf27
                © Nature Publishing Group 2005

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 8 November 2004
                : 30 March 2005
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                © The Author(s), under exclusive licence to Springer Nature America, Inc. 2005

                Medicine
                Medicine

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