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      Fully Human Immunoglobulin G From Transchromosomic Bovines Treats Nonhuman Primates Infected With Ebola Virus Makona Isolate

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          Abstract

          Transchromosomic bovines (Tc-bovines) adaptively produce fully human polyclonal immunoglobulin (Ig)G antibodies after exposure to immunogenic antigen(s). The National Interagency Confederation for Biological Research and collaborators rapidly produced and then evaluated anti-Ebola virus IgG immunoglobulins (collectively termed SAB-139) purified from Tc-bovine plasma after sequential hyperimmunization with an Ebola virus Makona isolate glycoprotein nanoparticle vaccine. SAB-139 was characterized by several in vitro production, research, and clinical level assays using wild-type Makona-C05 or recombinant virus/antigens from different Ebola virus variants. SAB-139 potently activates natural killer cells, monocytes, and peripheral blood mononuclear cells and has high-binding avidity demonstrated by surface plasmon resonance. SAB-139 has similar concentrations of galactose-α-1,3-galactose carbohydrates compared with human-derived intravenous Ig, and the IgG1 subclass antibody is predominant. All rhesus macaques infected with Ebola virus/H.sapiens-tc/GIN/2014/Makona-C05 and treated with sufficient SAB-139 at 1 day (n = 6) or 3 days (n = 6) postinfection survived versus 0% of controls. This study demonstrates that Tc-bovines can produce pathogen-specific human Ig to prevent and/or treat patients when an emerging infectious disease either threatens to or becomes an epidemic.

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          Most cited references37

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          Polyfunctional HIV-Specific Antibody Responses Are Associated with Spontaneous HIV Control

          Elite controllers (ECs) represent a unique model of a functional cure for HIV-1 infection as these individuals develop HIV-specific immunity able to persistently suppress viremia. Because accumulating evidence suggests that HIV controllers generate antibodies with enhanced capacity to drive antibody-dependent cellular cytotoxicity (ADCC) that may contribute to viral containment, we profiled an array of extra-neutralizing antibody effector functions across HIV-infected populations with varying degrees of viral control to define the characteristics of antibodies associated with spontaneous control. While neither the overall magnitude of antibody titer nor individual effector functions were increased in ECs, a more functionally coordinated innate immune–recruiting response was observed. Specifically, ECs demonstrated polyfunctional humoral immune responses able to coordinately recruit ADCC, other NK functions, monocyte and neutrophil phagocytosis, and complement. This functionally coordinated response was associated with qualitatively superior IgG3/IgG1 responses, whereas HIV-specific IgG2/IgG4 responses, prevalent among viremic subjects, were associated with poorer overall antibody activity. Rather than linking viral control to any single activity, this study highlights the critical nature of functionally coordinated antibodies in HIV control and associates this polyfunctionality with preferential induction of potent antibody subclasses, supporting coordinated antibody activity as a goal in strategies directed at an HIV-1 functional cure.
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            High-throughput, multiplexed IgG subclassing of antigen-specific antibodies from clinical samples.

            In vivo, the activity of antibodies relies critically on properties of both the variable domain, responsible for antigen recognition, and the constant domain, responsible for innate immune recognition. Here, we describe a flexible, microsphere-based array format for capturing information about both functional ends of disease-specific antibodies from complex, polyclonal clinical serum samples. Using minimal serum, we demonstrate IgG subclass profiling of multiple antibody specificities. We further capture and determine the subclass of epitope-specific antibodies. The data generated in this array provides a profile of the humoral immune response with multi-dimensional metrics regarding properties of both variable and constant IgG domains. Significantly, these properties are assessed simultaneously, and therefore information about the relationship between variable and constant domain characteristics is captured, and can be used to predict functions such as antibody effector activity.
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              Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant.

              No countermeasures currently exist for the prevention or treatment of the severe sequelae of Filovirus (such as Ebola virus; EBOV) infection. To overcome this limitation in our biodefense preparedness, we have designed monoclonal antibodies (mAbs) which could be used in humans as immunoprotectants for EBOV, starting with a murine mAb (13F6) that recognizes the heavily glycosylated mucin-like domain of the virion-attached glycoprotein (GP). Point mutations were introduced into the variable region of the murine mAb to remove predicted human T-cell epitopes, and the variable regions joined to human constant regions to generate a mAb (h-13F6) appropriate for development for human use. We have evaluated the efficacy of three variants of h-13F6 carrying different glycosylation patterns in a lethal mouse EBOV challenge model. The pattern of glycosylation of the various mAbs was found to correlate to level of protection, with aglycosylated h-13F6 providing the least potent efficacy (ED(50) = 33 μg). A version with typical heterogenous mammalian glycoforms (ED(50) = 11 μg) had similar potency to the original murine mAb. However, h-13F6 carrying complex N-glycosylation lacking core fucose exhibited superior potency (ED(50) = 3 μg). Binding studies using Fcγ receptors revealed enhanced binding of nonfucosylated h-13F6 to mouse and human FcγRIII. Together the results indicate the presence of Fc N-glycans enhances the protective efficacy of h-13F6, and that mAbs manufactured with uniform glycosylation and a higher potency glycoform offer promise as biodefense therapeutics.
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                Author and article information

                Journal
                J Infect Dis
                J. Infect. Dis
                jid
                The Journal of Infectious Diseases
                Oxford University Press (US )
                0022-1899
                1537-6613
                15 December 2018
                16 July 2018
                16 July 2018
                : 218
                : Suppl 5 , Marburg and Ebola Viruses: Marking 50 Years Since Discovery
                : S636-S648
                Affiliations
                [1 ]Viral and Rickettsial Diseases Department, Naval Medical Research Center, The Henry Jackson Foundation for the Advancement of Military Medicine, Silver Spring, Maryland
                [2 ]Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland
                [3 ]Novavax, Inc., Gaithersburg, Maryland
                [4 ]Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland
                [5 ]Biological Defense Research Directorate, Naval Medical Research Center, Ft. Detrick, Maryland
                [6 ]SAB Biotherapeutics Inc., Sioux Falls, South Dakota
                [7 ]Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland
                [8 ]Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston
                [9 ]Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
                Author notes

                Present Affiliation: DSI, Minneapolis, Minnesota.

                Present Affiliation: MRIGlobal-Global Health Surveillance and Diagnostics, Gaithersburg, Maryland.

                Correspondence: E. Sullivan, PhD, 2301 E. 60th St N., Sioux Falls, SD 57104 ( esullivan@ 123456sabbiotherapeutics.com ).
                Article
                jiy377
                10.1093/infdis/jiy377
                6249570
                30010950
                38af3f2c-2094-45f8-a33c-7036730dc565
                © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 13
                Funding
                Funded by: Division of Intramural Research, National Institute of Allergy and Infectious Diseases 10.13039/100006492
                Funded by: Division of Clinical Research
                Funded by: Integrated Research Facility and Battelle Memorial Institute’s prime contract with NIAID
                Award ID: HHSN272200700016I
                Funded by: Naval Medical Research Center 10.13039/100007680
                Funded by: Viral and Rickettsial Diseases Department and Biologic Defense Research Directorate
                Award ID: N62645-14-C-4034
                Funded by: The Henry Jackson Foundation for the Advancement of Military Medicine
                Funded by: US Navy
                Award ID: Omnibus III DO-0005
                Funded by: SAB Biotherapeutics Inc
                Categories
                Supplement Articles
                Treatment

                Infectious disease & Microbiology
                ebola; therapeutic; countermeasure; rhesus; bovine

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