Multifunctional Pan-ebolavirus Antibody Recognizes a Site of Broad Vulnerability on the Ebolavirus Glycoprotein

Gilchuk, Pavlo; Kuzmina, Natalia; Ilinykh, Philipp A.; Huang, Kai; Gunn, Bronwyn M.; Bryan, Aubrey L.; Davidson, Edgar; Doranz, Benjamin J.; Turner, Hannah L.; Fusco, Marnie L.; Vilain, Éric; Hoff, Nicole A.; Binshtein, Elad; Kose, Nurgun; Flyak, Andrew I.; Flinko, Robin; Orlandi, Chiara; Carnahan, Robert H.; Parrish, Erica H.; Sevy, Alexander M.; Bombardi, Robin; Singh, Prashant K.; Mukadi, Patrick; Muyembe-Tamfum, Jean Jacques; Ohi, Melanie D.; Saphire, Erica Ollmann; Lewis, George K.; Alter, Galit; Ward, Andrew B.; Rimoin, Anne W.; Bukreyev, Alexander

doi:10.1016/j.immuni.2018.06.018

Cited by 69 publications

(100 citation statements)

References 52 publications

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“…If the GP was treated with thermolysin first, all nine GC-specific antibodies showed greatly reduced binding ( Figures 2C and S2). A similar observation was made recently for the GC-specific mAb EBOV-442 (Gilchuk et al, 2018). Although not definitive, these results suggest that some antibodies bound to the glycan cap may neutralize either through interference with cathepsin cleavage or by stabilizing the glycan cap in the bound state despite thermolysin cleavage.…”

Section: Discussionsupporting

confidence: 86%

“…These results suggested that the P6, 040, and other neutralizing GC-specific antibodies may have either inhibited cleavage of GP by thermolysin or stabilized the glycan cap in the bound state despite cleavage. A related observation has been made recently with the GC-specific mAb EBOV-442 (Gilchuk et al, 2018).…”

Section: Mucin-like Domain-dependent Antibodiessupporting

confidence: 63%

“…Mixtures of monoclonal antibodies to the EBOV glycoprotein (GP) from convalescent humans (Maruyama et al, 1999;Flyak et al, 2016Flyak et al, , 2018Corti et al, 2016;Bornholdt et al, 2016;Wec et al, 2017;Gilchuk et al, 2018), humanized mice (Pascal et al, 2018), hyper-immunized macaques (Keck et al, 2015;Zhao et al, 2017), and wild-type mice (Furuyama et al, 2016;Marzi et al, 2012;Wilson et al, 2000;Qiu et al, 2012;Pettitt et al, 2013;Takada et al, 2007) have been shown to be therapeutic in various animal models. The antibodies of human origin, 114 (to the receptor binding region) and 100 (to the base), showed a similarly profound therapeutic effect (Corti et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Monoclonal Antibodies for Ebola Virus Infection Derived from Vaccinated Humans

et al. 2019

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Section: Discussionsupporting

confidence: 86%

Section: Mucin-like Domain-dependent Antibodiessupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

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Therapeutic Monoclonal Antibodies for Ebola Virus Infection Derived from Vaccinated Humans

et al. 2019

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“…Such antibodies may as well offer cross-protection against related viruses. Antibodies targeting conserved epitopes in the stem regions of glycoproteins of the enveloped virus including influenza virus and ebolavirus offer protection against a wide range of antigenically distinct variants [46][47][48]. Likewise, the generation of antibodies targeting the conserved S2 stem of the coronavirus spike protein that can cross-bind spikes of related coronaviruses may even allow the development of mAbs with broad protection against related future emerging coronaviruses.…”

Section: Discussionmentioning

confidence: 99%

Towards a solution to MERS: protective human monoclonal antibodies targeting different domains and functions of the MERS-coronavirus spike glycoprotein

Widjaja

Wang

Haperen

et al. 2019

Emerging Microbes & Infections

115

152

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The Middle-East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic virus that causes severe and often fatal respiratory disease in humans. Efforts to develop antibody-based therapies have focused on neutralizing antibodies that target the receptor binding domain of the viral spike protein thereby blocking receptor binding. Here, we developed a set of human monoclonal antibodies that target functionally distinct domains of the MERS-CoV spike protein. These antibodies belong to six distinct epitope groups and interfere with the three critical entry functions of the MERS-CoV spike protein: sialic acid binding, receptor binding and membrane fusion. Passive immunization with potently as well as with poorly neutralizing antibodies protected mice from lethal MERS-CoV challenge. Collectively, these antibodies offer new ways to gain humoral protection in humans against the emerging MERS-CoV by targeting different spike protein epitopes and functions.

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“…These are, to our knowledge, the lowest single doses (0.8-1.3 mg total mAb) and longest post-exposure treatment windows (4-5 days) demonstrated to protect guinea pigs from lethal ebolavirus challenge. All previous studies with both therapeutic mAbs and mAb cocktails used total doses of 5-10 mg and did not report initial mAb treatments past 3 days post-exposure 15,16,[33][34][35][36] .…”

mentioning

confidence: 99%

Human antibody cocktail deploys multiple functions to confer pan-ebolavirus protection

et al. 2018

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Africa and in its aftermath, the passive administration of monoclonal antibodies (mAbs) emerged as a promising treatment approach [1][2][3][4][5][6][7] . However, all antibody-based therapeutics currently in advanced development are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against divergent outbreak-causing ebolaviruses, including Bundibugyo virus (BDBV) and Sudan virus (SUDV) 2,3,5,7 . Here we advance MBP134, a cocktail of two broadly neutralizing human mAbs targeting the filovirus surface glycoprotein, GP, as a candidate pan-ebolavirus therapeutic. One component of this cocktail is a pan-ebolavirus neutralizing mAb, ADI-15878, isolated from a human EVD survivor 8,9 . The second, ADI-23774, was derived by affinity maturation of a human mAb 8,9 via yeast display to enhance its potency against SUDV. MBP134 afforded exceptionally potent pan-ebolavirus neutralization in vitro and demonstrated greater protective efficacy than ADI-15878 alone in the guinea pig model of lethal EBOV challenge.A second-generation cocktail, MBP134 AF , engineered to effectively harness natural killer (NK) cells afforded additional, unprecedented improvements in protective efficacy against EBOV and SUDV in guinea pigs relative to both its precursor and to any mAbs or mAb cocktails tested previously. MBP134 AF is a best-in-class mAb cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates.We previously isolated and characterized 349 GP-specific mAbs from a survivor of the West African EVD epidemic 9 . A systematic analysis of this library for breadth of the neutralizing mAb response against ebolaviruses identified ADI-15878 as a promising candidate therapeutic 8 .ADI-15878 possesses potent pan-ebolavirus neutralizing activity through its recognition of a 2

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Multifunctional Pan-ebolavirus Antibody Recognizes a Site of Broad Vulnerability on the Ebolavirus Glycoprotein

Cited by 69 publications

References 52 publications

Therapeutic Monoclonal Antibodies for Ebola Virus Infection Derived from Vaccinated Humans

Therapeutic Monoclonal Antibodies for Ebola Virus Infection Derived from Vaccinated Humans

Towards a solution to MERS: protective human monoclonal antibodies targeting different domains and functions of the MERS-coronavirus spike glycoprotein

Human antibody cocktail deploys multiple functions to confer pan-ebolavirus protection

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