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  • 1
    Language: English
    In: Analytical chemistry, 21 August 2012, Vol.84(16), pp.7227-32
    Description: Native mass spectrometry was evaluated for the qualitative and semiquantitative analysis of composite mixtures of antibodies representing biopharmaceutical products coexpressed from single cells. We show that by using automated peak fitting of the ion signals in the native mass spectra, we can quantify the relative abundance of each of the antibodies present in mixtures, with an average accuracy of 3%, comparable to a cation exchange chromatography based approach performed in parallel. Moreover, using native mass spectrometry we were able to identify, separate, and quantify 9 antibodies present in a complex mixture of 10 antibodies, whereas this complexity could not be unraveled by cation exchange chromatography. Native mass spectrometry presents a valuable alternative to existing analytical methods for qualitative and semiquantitative profiling of biopharmaceutical products. It provides both the identity of each species in a mixture by mass determination and the relative abundance through comparison of relative ion signal intensities. Native mass spectrometry is a particularly effective tool for characterization of heterogeneous biopharmaceutical products such as bispecific antibodies and antibody mixtures.
    Keywords: Antibodies -- Analysis ; Spectrometry, Mass, Electrospray Ionization -- Methods
    ISSN: 00032700
    E-ISSN: 1520-6882
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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, 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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  • 4
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 December 2015, Vol.21(24), pp.5519-31
    Description: Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that cotargeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular underpinnings of this synergy to identify key vulnerabilities susceptible to alternative therapeutic opportunities. The phosphorylation/activation of HER2, HER3, EGFR (HER receptors), and downstream transducers was evaluated in HER2-overexpressing colorectal and gastric cancer cell lines by Western blotting and/or multiplex phosphoproteomics. The in vivo outcome of antibody-mediated HER2 blockade by trastuzumab, reversible HER2 inhibition by lapatinib, and irreversible HER2 inhibition by afatinib was assessed in patient-derived tumorgrafts and cell-line xenografts by monitoring tumor growth curves and by using antibody-based proximity assays. Trastuzumab monotherapy reduced HER3 phosphorylation, with minor consequences on downstream transducers. Lapatinib alone acutely inhibited all HER receptors and effectors but led to delayed rephosphorylation of HER3 and EGFR and partial restoration of ERK and AKT activity. When combined with lapatinib, trastuzumab prevented HER3/EGFR reactivation and caused prolonged inhibition of ERK/AKT. Afatinib alone was also very effective in counteracting the reinstatement of HER3, EGFR, and downstream signaling activation. In vivo, the combination of trastuzumab and lapatinib-or, importantly, monotherapy with afatinib-resulted in overt tumor shrinkage. Only prolonged inhibition of HER3 and EGFR, achievable by dual blockade with trastuzumab and lapatinib or irreversible HER2 inhibition by single-agent afatinib, led to regression of HER2-amplified gastrointestinal carcinomas. Clin Cancer Res; 21(24); 5519-31. ©2015 AACR.
    Keywords: Antineoplastic Agents -- Pharmacology ; Carcinoma -- Genetics ; Erbb Receptors -- Antagonists & Inhibitors ; Gastrointestinal Neoplasms -- Genetics ; Protein Kinase Inhibitors -- Pharmacology ; Receptor, Erbb-2 -- Genetics ; Receptor, Erbb-3 -- Antagonists & Inhibitors
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 5
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  • 7
    Language: English
    In: Cancer Immunology Research, 11/2016, Vol.4(11 Supplement), pp.B088-B088
    ISSN: 2326-6066
    E-ISSN: 2326-6074
    Source: CrossRef
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  • 8
    In: Future Virology, September 2009, Vol.4(5), p.419-422
    Description: Evaluation of: Sultana H, Foellmer HG, Neelakanta G et al. : Fusion loop peptide of the West Nile virus envelope protein is essential for pathogenesis and is recognized by a therapeutic cross-reactive human monoclonal antibody. J. Immunol. 183(1), 650–660 (2009) . Flaviviruses, such as West Nile virus, the dengue serotypes, Japanese encephalitis virus and yellow fever virus are important human pathogens and can co-circulate in parts of the world. Humoral immunity is important in the mammalian protective response to flaviviruses and passive immunization has been shown to be effective in preventing infection and even treating disease. Monoclonal antibodies (mAbs) against flaviviruses can be divided basically into potent neutralizing mAbs with restricted flavivirus cross-reactivity and broadly cross-reactive mAbs with low neutralizing potency and protective activity. Here, Sultana and colleagues extend the characterization of the cross-reactive mAb11 by defining its epitope within the fusion loop of the West Nile virus envelope protein and link the reduced neuroinvasiveness of a mAb11 neutralization escape variant to a diminished ability to activate Toll-like receptor 3, induce inflammatory cytokine release and compromise blood–brain barrier integrity. The results highlight the importance of the fusion loop in viral pathogenesis; however, challenges remain to develop mAb11 into a viable therapeutic. Instead, mixtures of potent neutralizing mAbs with different flavivirus specificities may be a more feasible approach toward a broadly active flavivirus therapeutic antibody product.
    Keywords: Virus;
    ISSN: 1746-0794
    E-ISSN: 1746-0808
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  • 9
  • 10
    Language: English
    In: Biotechnology and Bioengineering, 01 August 2010, Vol.106(5), pp.741-750
    Description: Therapeutic monoclonal antibodies, a highly successful class of biological drugs, are conventionally manufactured in mammalian cell lines. A recent approach to increase the therapeutic effectiveness of monoclonal antibodies has been to combine two or more of them; however this increases the complexity of development and manufacture. To address this issue a method to efficiently express multiple monoclonal antibodies from a single cell has been developed and we describe here the generation of stable cell clones that express high levels of a human monoclonal antibody mixture. PER.C6® cells were transfected with a combination of plasmids containing genes encoding three different antibodies. Clones that express the three corresponding antibody specificities were identified, subcloned, and passaged in the absence of antibiotic selection pressure. At several time points, batch production runs were analyzed for stable growth and IgG production characteristics. The majority (11/12) of subclones analyzed expressed all three antibody specificities in constant ratios with total IgG productivity ranging between 15 and 20 pg/cell/day under suboptimal culture conditions after up to 67 population doublings. The growth and IgG production characteristics of the stable clones reported here resemble those of single monoclonal antibody cell lines from conventional clone generation programs. We conclude that the methodology described here is applicable to the generation of stable PER.C6® clones for industrial scale production of mixtures of antibodies. Biotechnol. Bioeng. 2010;106: 741–750. © 2010 Wiley Periodicals, Inc.
    Keywords: Antibody Mixtures ; Per.C6® ; Oligoclonics™ ; Clonal Cell Lines
    ISSN: 0006-3592
    E-ISSN: 1097-0290
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