Molecular Characterization of the Monoclonal Antibodies Composing ZMAb: A Protective Cocktail Against Ebola Virus

Audet, Jonathan; Wong, Gary; Wang, Han; Lu, Guangwen; Gao, George F.; Kobinger, Gary P.; Qiu, Xiangguo

doi:10.1038/srep06881

Cited by 95 publications

(80 citation statements)

References 23 publications

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“…opportunity for selection of escape mutants. Two of the antibodies in the ZMAb cocktail (c4G7 and c2G4) are neutralizing, whereas the third (c1H3) is nonneutralizing (22,26,36). None of the MB-003 mAbs are neutralizing in the absence of complement (29), but both ZMAb and MB-003 mixtures are protective (22,27).…”

mentioning

confidence: 99%

Structures of protective antibodies reveal sites of vulnerability on Ebola virus

Murin¹,

Fusco²,

Bornholdt³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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171

248

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Ebola virus (EBOV) and related filoviruses cause severe hemorrhagic fever, with up to 90% lethality, and no treatments are approved for human use. Multiple recent outbreaks of EBOV and the likelihood of future human exposure highlight the need for pre-and postexposure treatments. Monoclonal antibody (mAb) cocktails are particularly attractive candidates due to their proven postexposure efficacy in nonhuman primate models of EBOV infection. Two candidate cocktails, MB-003 and ZMAb, have been extensively evaluated in both in vitro and in vivo studies. Recently, these two therapeutics have been combined into a new cocktail named ZMapp, which showed increased efficacy and has been given compassionately to some human patients. Epitope information and mechanism of action are currently unknown for most of the component mAbs. Here we provide single-particle EM reconstructions of every mAb in the ZMapp cocktail, as well as additional antibodies from MB-003 and ZMAb. Our results illuminate key and recurring sites of vulnerability on the EBOV glycoprotein and provide a structural rationale for the efficacy of ZMapp. Interestingly, two of its components recognize overlapping epitopes and compete with each other for binding. Going forward, this work now provides a basis for strategic selection of next-generation antibody cocktails against Ebola and related viruses and a model for predicting the impact of ZMapp on potential escape mutations in ongoing or future Ebola outbreaks.

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mentioning

confidence: 99%

Structures of protective antibodies reveal sites of vulnerability on Ebola virus

Murin¹,

Fusco²,

Bornholdt³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

171

248

View full text Add to dashboard Cite

show abstract

“…In the absence of reverse genetics systems and/or biosafety level 4 (BSL-4) facilities required for work with filoviruses, researchers use various surrogate systems for characterization of filovirus-specific MAbs or investigation of various steps of filovirus life cycle involving GP. These systems include chimeric vesicular stomatitis Indiana viruses (VSV) with the G protein replaced with filovirus GP (19)(20)(21) and pseudotyped gammaretroviruses (22,23) and lentiviruses (24)(25)(26), which have their respective envelope proteins replaced with a filovirus GP provided in trans. It is generally assumed that these surrogate systems can be used to accurately characterize neutralizing properties of filovirus polyclonal or monoclonal antibodies.…”

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confidence: 99%

Chimeric Filoviruses for Identification and Characterization of Monoclonal Antibodies

Ilinykh

Shen

Flyak

et al. 2016

J Virol

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Recent experiments suggest that some glycoprotein (GP)-specific monoclonal antibodies (MAbs) can protect experimental animals against the filovirus Ebola virus (EBOV). There is a need for isolation of MAbs capable of neutralizing multiple filoviruses.Antibody neutralization assays for filoviruses frequently use surrogate systems such as the rhabdovirus vesicular stomatitis Indiana virus (VSV), lentiviruses or gammaretroviruses with their envelope proteins replaced with EBOV GP or pseudotyped with EBOV GP. It is optimal for both screening and in-depth characterization of newly identified neutralizing MAbs to generate recombinant filoviruses that express a reporter fluorescent protein in order to more easily monitor and quantify the infection. Our study showed that unlike neutralization-sensitive chimeric VSV, authentic filoviruses are highly resistant to neutralization by MAbs. We used reverse genetics techniques to replace EBOV GP with its counterpart from the heterologous filoviruses Bundibugyo virus (BDBV), Sudan virus, and even Marburg virus and Lloviu virus, which belong to the heterologous genera in the filovirus family. This work resulted in generation of multiple chimeric filoviruses, demonstrating the ability of filoviruses to tolerate swapping of the envelope protein. The sensitivity of chimeric filoviruses to neutralizing MAbs was similar to that of authentic biologically derived filoviruses with the same GP. Moreover, disabling the expression of the secreted GP (sGP) resulted in an increased susceptibility of an engineered virus to the BDBV52 MAb isolated from a BDBV survivor, suggesting a role for sGP in evasion of antibody neutralization in the context of a human filovirus infection. IMPORTANCEThe study demonstrated that chimeric rhabdoviruses in which G protein is replaced with filovirus GP, widely used as surrogate targets for characterization of filovirus neutralizing antibodies, do not accurately predict the ability of antibodies to neutralize authentic filoviruses, which appeared to be resistant to neutralization. However, a recombinant EBOV expressing a fluorescent protein tolerated swapping of GP with counterparts from heterologous filoviruses, allowing high-throughput screening of B cell lines to isolate MAbs of any filovirus specificity. Human MAb BDBV52, which was isolated from a survivor of BDBV infection, was capable of partially neutralizing a chimeric EBOV carrying BDBV GP in which expression of sGP was disabled. In contrast, the parental virus expressing sGP was resistant to the MAb. Thus, the ability of filoviruses to tolerate swapping of GP can be used for identification of neutralizing MAbs specific to any filovirus and for the characterization of MAb specificity and mechanism of action.T he family Filoviridae is composed of the genus Ebolavirus, which includes Ebola (EBOV), Sudan (SUDV), Taï Forest (TAFV), Reston (RESTV), and Bundibugyo (BDBV) viruses, the genus Marburgvirus, which includes Marburg (MARV) and Ravn (RAVV) viruses, and the putative genus Cuevavirus, which i...

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“…In addition, HIV virus can mutate rapidly and a patient who finally dies from HIVrelated infections may have multiple strains of the same virus [33]. The same phenomenon is common in the Ebola virus, where the virus mutates, but not at the same rate of mutation and pace as the HIV, due to several factors [35].…”

Section: Discussionmentioning

confidence: 99%

Fostering prevention and care delivery services capability on HIV pandemic and Ebola outbreak symbiosis in Africa

Tambo

Yah

Ugwu

et al. 2016

J Infect Dev Ctries

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Human immunodeficiency virus (HIV) and the re-emerging Ebola virus disease (EVD) are closely intertwined and remain a persistent public health threat and global challenge. Their origin and rapid transmission and spread have similar boundaries and share overlapping impact characteristics, including related symptoms and other interactions. The controversies and global threat of these viruses require rapid response policy and evidence-based implementation findings. The constraints and dual burden inflicted by Ebola and HIV infections are highly characterized by similar socio-demographics, socio-economic and political factors. EVD has similar effects and burdens to HIV infection. This study seeks to understand EVD in the context of HIV epidemic despite the challenges in developing an effective vaccine against HIV and EVD. Our findings show that early understanding, prevention and treatment of these diseases a global health threat mainly in Africa is important and valuable. The lessons learned so far from HIV and Ebola epidemics are crucial in health programming and execution of rapid response interventions and continued vigilance against EVD before it become another worldwide health menace. Therefore, the current regional West Africa EVD requires strengthening healthcare systems and building preparedness and response capacity. Importantly, appropriate community participation, health education and resilience coupled with deployment of effective novel diagnostic approaches in early warning and surveillance of threats and emerging diseases. Therefore, there is an urgent need to develop novel key strategies are crucial in curbing the constant viral resurgence, persistence transmission dynamics and spread, as well in accelerating Ebola vaccines regimen (immunization) development and national implementation plans in achieving sustained control, and eventual elimination.

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Molecular Characterization of the Monoclonal Antibodies Composing ZMAb: A Protective Cocktail Against Ebola Virus

Cited by 95 publications

References 23 publications

Structures of protective antibodies reveal sites of vulnerability on Ebola virus

Structures of protective antibodies reveal sites of vulnerability on Ebola virus

Chimeric Filoviruses for Identification and Characterization of Monoclonal Antibodies

Fostering prevention and care delivery services capability on HIV pandemic and Ebola outbreak symbiosis in Africa

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