Characterization of Zaire ebolavirus glycoprotein-specific monoclonal antibodies

Qiu, Xiangguo; Alimonti, Judie B.; Melito, Pasquale L.; Fernando, Lisa; Ströher, Ute; Jones, Steven M.

doi:10.1016/j.clim.2011.08.008

Cited by 123 publications

(138 citation statements)

References 45 publications

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“…The results we obtained with GP 1-294 may be in part due to incorrect folding of this truncated protein or the fact that this domain may not be as well exposed on the complete, native sGP and GP proteins. However, these results were not surprising since previous studies demonstrated that significant humoral immunity targets other domains of GP, such as the mucin-like domain and the internal fusion loops (19,32,38,43). In contrast to the ELISA, Western blot analysis demonstrated no immunoreactivity against the two forms of GP in the group of Ebola virus patients.…”

Section: Discussioncontrasting

confidence: 46%

Profiling the Native Specific Human Humoral Immune Response to Sudan Ebola Virus Strain Gulu by Chemiluminescence Enzyme-Linked Immunosorbent Assay

Sobarzo

Perelman

Groseth

et al. 2012

Clin. Vaccine Immunol.

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Section: Discussioncontrasting

confidence: 46%

Profiling the Native Specific Human Humoral Immune Response to Sudan Ebola Virus Strain Gulu by Chemiluminescence Enzyme-Linked Immunosorbent Assay

Sobarzo

Perelman

Groseth

et al. 2012

Clin. Vaccine Immunol.

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“…The sequence identity between filovirus GPs is highest within the receptor binding region (RBR) (4) and GP2, suggesting that shared epitopes may exist within these domains. Several monoclonal antibodies (MAbs) against EBOV GP with protective efficacy in rodents and NHPs have been reported (5)(6)(7)(8)(9)(10)(11)(12). Neutralizing antibodies have also been described for SUDV with efficacy in a recently developed rodent model (13,14).…”

Section: F Iloviruses Consisting Of Marburg Virus (Marv) Ravn Virus mentioning

confidence: 99%

Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein

Keck

Enterlein

Howell

et al. 2016

J Virol

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Filoviruses cause highly lethal viral hemorrhagic fever in humans and nonhuman primates. Current immunotherapeutic options for filoviruses are mostly specific to Ebola virus (EBOV), although other members of Filoviridae such as Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have also caused sizeable human outbreaks. Here we report a set of pan-ebolavirus and pan-filovirus monoclonal antibodies (MAbs) derived from cynomolgus macaques immunized repeatedly with a mixture of engineered glycoproteins (GPs) and virus-like particles (VLPs) for three different filovirus species. The antibodies recognize novel neutralizing and nonneutralizing epitopes on the filovirus glycoprotein, including conserved conformational epitopes within the core regions of the GP1 subunit and a novel linear epitope within the glycan cap. We further report the first filovirus antibody binding to a highly conserved epitope within the fusion loop of ebolavirus and marburgvirus species. One of the antibodies binding to the core GP1 region of all ebolavirus species and with lower affinity to MARV GP cross neutralized both SUDV and EBOV, the most divergent ebolavirus species. In a mouse model of EBOV infection, this antibody provided 100% protection when administered in two doses and partial, but significant, protection when given once at the peak of viremia 3 days postinfection. Furthermore, we describe novel cocktails of antibodies with enhanced protective efficacy compared to individual MAbs. In summary, the present work describes multiple novel, cross-reactive filovirus epitopes and innovative combination concepts that challenge the current therapeutic models. IMPORTANCEFiloviruses are among the most deadly human pathogens. The 2014-2015 outbreak of Ebola virus disease (EVD) led to more than 27,000 cases and 11,000 fatalities. While there are five species of Ebolavirus and several strains of marburgvirus, the current immunotherapeutics primarily target Ebola virus. Since the nature of future outbreaks cannot be predicted, there is an urgent need for therapeutics with broad protective efficacy against multiple filoviruses. Here we describe a set of monoclonal antibodies cross-reactive with multiple filovirus species. These antibodies target novel conserved epitopes within the envelope glycoprotein and exhibit protective efficacy in mice. We further present novel concepts for combination of cross-reactive antibodies against multiple epitopes that show enhanced efficacy compared to monotherapy and provide complete protection in mice. These findings set the stage for further evaluation of these antibodies in nonhuman primates and development of effective pan-filovirus immunotherapeutics for use in future outbreaks. F iloviruses consisting of Marburg virus (MARV), Ravn virus (RAVV), and five species of ebolavirus, Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), Reston virus (RESTV), and Taï Forest virus (TAFV), are causative agents of severe hemorrhagic fever in humans and nonhuman primates (NHPs) (1, ...

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“…In enzyme-linked immunosorbent assays (ELISAs), mAb 2G4 bound to GP2, and 4G7 bound to epitopes in the C-terminal portion of GP1 of the EBOV-GP, whereas 1H3 bound to the soluble GP (sGP) portion (amino acids 1 to 295) (23). None of these EBOV-GP-specific mAbs are crossreactive with Marburg virus or other EBOV species but did react with other EBOV strains.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, we optimized a treatment protocol with three of eight EBOV glycoprotein (GP)-specific mAbs (1H3, 2G4, and 4G7) that were previously generated from mice vaccinated with the VSVDG/EBOV-GP vaccine (23,24). In enzyme-linked immunosorbent assays (ELISAs), mAb 2G4 bound to GP2, and 4G7 bound to epitopes in the C-terminal portion of GP1 of the EBOV-GP, whereas 1H3 bound to the soluble GP (sGP) portion (amino acids 1 to 295) (23).…”

Section: Introductionmentioning

confidence: 99%

Successful Treatment of Ebola Virus–Infected Cynomolgus Macaques with Monoclonal Antibodies

et al. 2012

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Characterization of Zaire ebolavirus glycoprotein-specific monoclonal antibodies

Cited by 123 publications

References 45 publications

Profiling the Native Specific Human Humoral Immune Response to Sudan Ebola Virus Strain Gulu by Chemiluminescence Enzyme-Linked Immunosorbent Assay

Profiling the Native Specific Human Humoral Immune Response to Sudan Ebola Virus Strain Gulu by Chemiluminescence Enzyme-Linked Immunosorbent Assay

Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein

Successful Treatment of Ebola Virus–Infected Cynomolgus Macaques with Monoclonal Antibodies

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