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Berlin Brandenburg

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  • 1
    Language: English
    In: Science (New York, N.Y.), 12 August 2011, Vol.333(6044), pp.843-50
    Description: Current flu vaccines provide only limited coverage against seasonal strains of influenza viruses. The identification of V(H)1-69 antibodies that broadly neutralize almost all influenza A group 1 viruses constituted a breakthrough in the influenza field. Here, we report the isolation and characterization of a human monoclonal antibody CR8020 with broad neutralizing activity against most group 2 viruses, including H3N2 and H7N7, which cause severe human infection. The crystal structure of Fab CR8020 with the 1968 pandemic H3 hemagglutinin (HA) reveals a highly conserved epitope in the HA stalk distinct from the epitope recognized by the V(H)1-69 group 1 antibodies. Thus, a cocktail of two antibodies may be sufficient to neutralize most influenza A subtypes and, hence, enable development of a universal flu vaccine and broad-spectrum antibody therapies.
    Keywords: Antibodies, Monoclonal -- Immunology ; Antibodies, Neutralizing -- Immunology ; Antibodies, Viral -- Immunology ; Antigens, Viral -- Immunology ; Hemagglutinin Glycoproteins, Influenza Virus -- Immunology ; Influenza A Virus -- Immunology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 January 2014, Vol.111(1), pp.445-50
    Description: The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.
    Keywords: X-Ray Crystallography ; Antibody Recognition ; Electron Microscopy ; Antibodies, Neutralizing -- Immunology ; Antibodies, Viral -- Immunology ; Influenza A Virus -- Chemistry
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Science, 25 April 2013, Vol.337(9, 2012)
    Description: Influenza Antibodies, Part BWith its ability to reassort in animal hosts like pigs and birds, and to cause pandemics, influenza A viruses are often in the spotlight. However, a substantial portion of the annual flu burden is also the result of influenza B virus, which is a single influenza type that is characterized by two antigenically and genetically distinct lineages. Dreyfus et al. (p. 1343, published online 9 August) identify three monoclonal human antibodies that are able to protect against lethal infection with both lineages of influenza B virus in mice. Two antibodies, which bind to distinct regions of the viral hemagluttinin (HA) molecule, neutralize multiple strains from both lineages of influenza B virus, whereas the third antibody binds to the stem region of HA and is able to neutralize both influenza A and B strains. The structural data from these antibodies bound to HA, together with already known antibodies targeting influenza A, may provide clues for designing a universal vaccine to protect against both influenza virus types.
    Keywords: Influenza ; Hydroxyapatite ; Antibodies ; Human ; Viruses ; Vaccines ; Pigs ; Strain ; Miscellaneous Sciences (So);
    ISSN: 00368075
    E-ISSN: 10959203
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  • 4
    Language: English
    In: Science, 21 May 2009, Vol.324(2009)
    Description: Influenza virus presents an important and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Cocrystal structures were determined at 2.2 and 2.7 angstrom resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1 and HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.
    Keywords: 60 Applied LIFE Sciences ; Antibodies ; Antigens ; Channeling ; Complexes ; Human Populations ; Immunity ; Implementation ; Influenza ; Lethal Mutations ; Membranes ; Public Health ; Safety ; Surfaces ; Vaccines ; Viruses ; Sciences (General) ; Public Health
    ISSN: 0193-4511
    ISSN: 00368075
    E-ISSN: 10959203
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  • 5
    Language: English
    In: Science, 01 November 2018, Vol.362(6414)
    Description: Broadly neutralizing antibodies against highly variable pathogens have stimulated the design of vaccines and therapeutics. We report the use of diverse camelid single-domain antibodies to influenza virus hemagglutinin to generate multidomain antibodies with impressive breadth and potency. Multidomain antibody MD3606 protects mice against influenza A and B infection when administered intravenously or expressed locally from a recombinant adeno-associated virus vector. Crystal and single-particle electron microscopy structures of these antibodies with hemagglutinins from influenza A and B viruses reveal binding to highly conserved epitopes. Collectively, our findings demonstrate that multidomain antibodies targeting multiple epitopes exhibit enhanced virus cross-reactivity and potency. In combination with adeno-associated virus–mediated gene delivery, they may provide an effective strategy to prevent infection with influenza virus and other highly variable pathogens.
    Keywords: Sciences (General) ; Biology
    ISSN: 0036-8075
    E-ISSN: 1095-9203
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  • 6
    Language: English
    In: Science (New York, N.Y.), 08 March 2019, Vol.363(6431)
    Description: Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted three-dimensional cell culture of fully differentiated human bronchial epithelial cells. Cocrystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.
    Keywords: Antibodies, Neutralizing -- Chemistry ; Biomimetic Materials -- Pharmacology ; Influenza A Virus, H1n1 Subtype -- Drug Effects ; Influenza, Human -- Prevention & Control ; Piperazines -- Pharmacology ; Viral Fusion Protein Inhibitors -- Pharmacology ; Virus Internalization -- Drug Effects
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 7
    Language: English
    In: PLoS ONE, 2008, Vol.3(12), p.e3942
    Description: The hemagglutinin (HA) glycoprotein is the principal target of protective humoral immune responses to influenza virus infections but such antibody responses only provide efficient protection against a narrow spectrum of HA antigenic variants within a given virus subtype. Avian influenza viruses such as H5N1 are currently panzootic and pose a pandemic threat. These viruses are antigenically diverse and protective strategies need to cross protect against diverse viral clades. Furthermore, there are 16 different HA subtypes and no certainty the next pandemic will be caused by an H5 subtype, thus it is important to develop prophylactic and therapeutic interventions that provide heterosubtypic protection. ; Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge. ; The human monoclonal CR6261 described in this study could be developed for use as a broad spectrum agent for prophylaxis or treatment of human or avian influenza infections without prior strain characterization. Moreover, the CR6261 epitope could be applied in targeted vaccine strategies or in the design of novel antivirals. Finally our approach of screening the IgM memory repertoire could be applied to identify conserved and functionally relevant targets on other rapidly evolving pathogens.
    Keywords: Research Article ; Biotechnology ; Immunology -- Immunity To Infections ; Immunology -- Innate Immunity ; Microbiology -- Innate Immunity ; Virology -- Antivirals, Including Modes Of Action And Resistance ; Virology -- New Therapies, Including Antivirals And Immunotherapy ; Infectious Diseases -- Respiratory Infections ; Infectious Diseases -- Viral Infections ; Respiratory Medicine -- Respiratory Infections
    E-ISSN: 1932-6203
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  • 8
    In: The Journal of Virology, 2009, Vol. 83(13), p.6494
    Description: West Nile virus (WNV) is a neurotropic flavivirus that is now a primary cause of epidemic encephalitis in North America. Studies of mice have demonstrated that the humoral immune response against WNV limits primary infection and protects against a secondary challenge. The most-potent neutralizing mouse monoclonal antibodies (MAbs) recognize an epitope on the lateral ridge of domain III (DIII-lr) of the envelope (E) protein. However, studies with serum from human patients show that antibodies against the DIII-lr epitope comprise, at best, a minor component of the human anti-WNV antibody response. Herein, we characterize in detail two WNV-specific human MAbs, CR4348 and CR4354, that were isolated from B-cell populations of convalescent patients. These MAbs strongly neutralize WNV infection of cultured cells, protect mice against lethal infection in vivo, and yet poorly recognize recombinant forms of the E protein. Instead, CR4348 and CR4354 bind determinants on intact WNV virions and subviral particles in a pH-sensitive manner, and neutralization is altered by mutations at the dimer interface in domain II and the hinge between domains I and II, respectively. CR4348 and CR4354 human MAbs neutralize infection at a postattachment step in the viral life cycle, likely by inhibiting acid-induced fusion within the endosome.
    Keywords: Virions ; Epidemics ; Monoclonal Antibodies ; Lymphocytes B ; Life Cycle ; Antibody Response ; Infection ; Encephalitis ; Endosomes ; Envelopes ; Envelope Protein ; Immune Response (Humoral) ; Mutation ; Ph Effects ; Epitopes ; West Nile Virus ; Flavivirus ; Immunology;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 9
    Language: English
    In: European Journal of Cancer, 2005, Vol.41(1), pp.178-187
    Description: Tumour-associated cell surface markers are potential targets for antibody-based therapies. We have obtained a panel of myeloid cell binding single chain variable fragments (scFv) by applying phage display selection on myeloid cell lines followed by a selection round on freshly isolated acute myeloid leukaemia (AML) blasts using flow cytometry. To identify the target antigens, the scFv were recloned and expressed in an IgG format and tested for their ability to immunoprecipitate cell surface proteins. The IgGs that reacted with distinct cell membrane extractable proteins were used in large-scale affinity purification of the target antigen followed by mass-spectrometry-based identification. Well-characterised cell surface antigens, such as leukocyte antigen-related receptor protein tyrosine phosphatase (LAR PTP) and activated leukocyte adhesion molecule (ALCAM) in addition to several unknown proteins, like ATAD3A, were identified. These experiments demonstrate that phage antibody selection in combination with affinity chromatography and mass spectrometry can be exploited successfully to identify novel antibody target molecules on malignant cells.
    Keywords: Phage Display ; Tumour Antigen ; Single Chain Fv ; Aml ; Myeloid ; Lar Ptp ; Alcam ; Atad3a ; Medicine
    ISSN: 0959-8049
    E-ISSN: 1879-0852
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  • 10
    In: The Journal of Virology, 2006, Vol. 80(14), p.6982
    Description: Monoclonal antibodies (MAbs) neutralizing West Nile Virus (WNV) have been shown to protect against infection in animal models and have been identified as a correlate of protection in WNV vaccine studies. In the present study, antibody repertoires from three convalescent WNV-infected patients were cloned into an scFv phage library, and 138 human MAbs binding to WNV were identified. One hundred twenty-one MAbs specifically bound to the viral envelope (E) protein and four MAbs to the premembrane (prM) protein. Enzyme-linked immunosorbent assay-based competitive-binding assays with representative E protein-specific MAbs demonstrated that 24/51 (47%) bound to domain II while only 4/51 (8%) targeted domain III. In vitro neutralizing activity was demonstrated for 12 MAbs, and two of these, CR4374 and CR4353, protected mice from lethal WNV challenge at 50% protective doses of 12.9 and 357 mu g/kg of body weight, respectively. Our data analyzing three infected individuals suggest that the human anti-WNV repertoire after natural infection is dominated by nonneutralizing or weakly neutralizing MAbs binding to domain II of the E protein, while domain III-binding MAbs able to potently neutralize WNV in vitro and in vivo are rare.
    Keywords: Phages ; Prm Protein ; Envelopes ; Data Processing ; Body Weight ; Monoclonal Antibodies ; Envelope Protein ; Animal Models ; Vaccines ; Infection ; Immunosorbents ; West Nile Virus ; Methods ; Monoclonal Antibodies, Hybridoma, Antigens;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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