title: Generation and characterization of protective antibodies to Marburg virus.
abstract: Marburg virus (MARV) and Ebola virus (EBOV) have been a source of epidemics and outbreaks for several decades. We present here the generation and characterization of the first protective antibodies specific for wild-type MARV. Non-human primates (NHP), cynomolgus macaques, were immunized with viral-replicon particles expressing the glycoproteins (GP) of MARV (Ci67 isolate). An antibody fragment (single-chain variable fragment, scFv) phage display library was built after four immunogen injections, and screened against the GP1-649of MARV. Sequencing of 192 selected clones identified 18 clones with distinct VHand VLsequences. Four of these recombinant antibodies (R4A1, R4B11, R4G2, and R3F6) were produced in the scFv-Fc format for in vivo studies. Mice that were challenged with wild-type Marburg virus (Ci67 isolate) receiving 100 µg of scFv-Fc on days -1, 1 and 3 demonstrated protective efficacies ranging from 75-100%. The amino-acid sequences of the scFv-Fcs are similar to those of their human germline counterparts, sharing an identity ranging between 68 and 100% to human germline immunoglobulin. These results demonstrate for the first time that recombinant antibodies offer protection against wild-type MARV, and suggest they may be promising candidates for further therapeutic development especially due to their human homology.
authors.affiliation: a US Army Medical Research Institute for Infectious Disease (USAMRIID) , Fort Detrick , MD , USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Froude
authors.affiliation: b Unite de Biotechnologie des Anticorps, Institut de Recherche Biomedicale des Armees [IRBA-CRSSA] , La Tronche , France.|c BIOTEM, Apprieu , France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Pelat
authors.affiliation: d Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik Braunschweig , Germany.|e YUMAB GmbH, Rebenring , Braunschweig , Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Miethe
authors.affiliation: a US Army Medical Research Institute for Infectious Disease (USAMRIID) , Fort Detrick , MD , USA.
authors.forename: Samantha E
authors.initials: SE
authors.lastname: Zak
authors.affiliation: f Department of Microbiology and Immunology , Albert Einstein College of Medicine , Bronx , NY , USA.
authors.forename: Anna Z
authors.initials: AZ
authors.lastname: Wec
authors.affiliation: f Department of Microbiology and Immunology , Albert Einstein College of Medicine , Bronx , NY , USA.
authors.forename: Kartik
authors.initials: K
authors.lastname: Chandran
authors.affiliation: a US Army Medical Research Institute for Infectious Disease (USAMRIID) , Fort Detrick , MD , USA.
authors.forename: Jennifer Mary
authors.initials: JM
authors.lastname: Brannan
authors.affiliation: a US Army Medical Research Institute for Infectious Disease (USAMRIID) , Fort Detrick , MD , USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Bakken
authors.affiliation: d Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik Braunschweig , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hust
authors.affiliation: b Unite de Biotechnologie des Anticorps, Institut de Recherche Biomedicale des Armees [IRBA-CRSSA] , La Tronche , France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Thullier
authors.affiliation: a US Army Medical Research Institute for Infectious Disease (USAMRIID) , Fort Detrick , MD , USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D000918:Antibody Specificity; D006801:Humans; D008252:Macaca fascicularis; D029024:Marburgvirus / Q000276:immunology*; D057127:Single-Chain Antibodies / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D057127:Single-Chain Antibodies
keywords: Antibody; Marburg; biodefense; ebola; filovirus; hemorrhagic; murine; protection; therapeutic