A multifunctional human monoclonal neutralizing antibody that targets a unique conserved epitope on influenza HA

Bangaru, Sandhya; Zhang, H.; Gilchuk, Iuliia M.; Voss, Thomas G.; Irving, Ryan P.; Gilchuk, Pavlo; Matta, Pranathi; Zhu, Xueyong; Lang, Shanshan; Nieusma, Travis; Richt, Jüergen A.; Albrecht, Randy A.; Vanderven, Hillary A.; Bombardi, Robin; Kent, Stephen J.; Ward, Andrew B.; Wilson, Ian A.; Crowe, James E.

doi:10.1038/s41467-018-04704-9

Cited by 82 publications

(76 citation statements)

References 71 publications

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“…Preparation of recombinant H7.5 antibodies. H7.5 Fab for crystallization was prepared as previously described (27). In brief, the heavy and light chains of H7.5 were cloned independently into the phCMV3 vector and fused with an N-terminal IgK secretion signal.…”

Section: Methodsmentioning

confidence: 99%

Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor binding head domains

Turner

Pallesen

Lang

et al. 2018

Preprint

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Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy to decipher the mechanism of action of a potent HA head-directed monoclonal antibody bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, pre-fusion conformation that typifies all HA structures to date.Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the pre-fusion conformation. The "breathing" of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously. Author SummaryA transiently exposed epitope on influenza H7 hemagglutinin represents a new target for neutralizing antibodies.

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Section: Methodsmentioning

confidence: 99%

Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor binding head domains

Turner

Pallesen

Lang

et al. 2018

Preprint

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“…A range of antibodies targeting all three influenza A virus surface proteins (HA, NA and matrix protein) have been demonstrated to be effective when used for treatment in animal models including mice, ferrets or primates, with some antibodies entering efficacy evaluation in swine and even humans [1,3,5,31,[33][34][35]. Nevertheless, HA remains the main target protein for antibodies displaying therapeutic efficacy due to the antigen availability on the virus particle surface.…”

Section: Discussionmentioning

confidence: 99%

Engineered Recombinant Single Chain Variable Fragment of Monoclonal Antibody Provides Protection to Chickens Infected with H9N2 Avian Influenza

et al. 2020

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Passive immunisation with neutralising antibodies can be a potent therapeutic strategy if used pre-or post-exposure to a variety of pathogens. Herein, we investigated whether recombinant monoclonal antibodies (mAbs) could be used to protect chickens against avian influenza. Avian influenza viruses impose a significant economic burden on the poultry industry and pose a zoonotic infection risk for public health worldwide. Traditional control measures including vaccination do not provide rapid protection from disease, highlighting the need for alternative disease mitigation measures. In this study, previously generated neutralizing anti-H9N2 virus monoclonal antibodies were converted to single-chain variable fragment antibodies (scFvs). These recombinant scFv antibodies were produced in insect cell cultures and the preparations retained neutralization capacity against an H9N2 virus in vitro. To evaluate recombinant scFv antibody efficacy in vivo, chickens were passively immunized with scFvs one day before, and for seven days after virus challenge. Groups receiving scFv treatment showed partial virus load reductions measured by plaque assays and decreased disease manifestation. These results indicate that antibody therapy could reduce clinical disease and shedding of avian influenza virus in infected chicken flocks.

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“…Vestigial esterase domain-binding antibodies were reported to function mainly by blocking viral egress similar to NA inhibitors [89,101]. Recent studies indicated that vestigial esterase domain-binding antibodies also elicit ADCC that may help to protect against viral infection [102]. Bangaru and colleagues found a monoclonal antibody, H3v-47, that not only can neutralize diverse H3N2 viruses and block progeny viruses release, but also induce potent ADCC activity, suggesting that Fc-effector functions are critical for both HA head and stalk targeting antibodies [102].…”

Section: Hi-negative Head-targeting Mabs Can Mediate Robust Adcc Actimentioning

confidence: 99%

“…Recent studies indicated that vestigial esterase domain-binding antibodies also elicit ADCC that may help to protect against viral infection [102]. Bangaru and colleagues found a monoclonal antibody, H3v-47, that not only can neutralize diverse H3N2 viruses and block progeny viruses release, but also induce potent ADCC activity, suggesting that Fc-effector functions are critical for both HA head and stalk targeting antibodies [102]. Interestingly, these researchers found that this multifunctional antibody can recognize a novel epitope that spans the vestigial esterase and receptor-binding subdomains.…”

Section: Hi-negative Head-targeting Mabs Can Mediate Robust Adcc Actimentioning

confidence: 99%

Influenza A Virus Antibodies with Antibody-Dependent Cellular Cytotoxicity Function

Gao

Sheng

Sreenivasan

et al. 2020

Viruses

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Influenza causes millions of cases of hospitalizations annually and remains a public health concern on a global scale. Vaccines are developed and have proven to be the most effective countermeasures against influenza infection. Their efficacy has been largely evaluated by hemagglutinin inhibition (HI) titers exhibited by vaccine-induced neutralizing antibodies, which correlate fairly well with vaccine-conferred protection. Contrarily, non-neutralizing antibodies and their therapeutic potential are less well defined, yet, recent advances in anti-influenza antibody research indicate that non-neutralizing Fc-effector activities, especially antibody-dependent cellular cytotoxicity (ADCC), also serve as a critical mechanism in antibody-mediated anti-influenza host response. Monoclonal antibodies (mAbs) with Fc-effector activities have the potential for prophylactic and therapeutic treatment of influenza infection. Inducing mAbs mediated Fc-effector functions could be a complementary or alternative approach to the existing neutralizing antibody-based prevention and therapy. This review mainly discusses recent advances in Fc-effector functions, especially ADCC and their potential role in influenza countermeasures. Considering the complexity of anti-influenza approaches, future vaccines may need a cocktail of immunogens in order to elicit antibodies with broad-spectrum protection via multiple protective mechanisms.Viruses 2020, 12, 276 2 of 20 the infected cell, HA on the virion still interacts with the SA receptors on the host cell membrane. The tetrameric NA spike functions to release the viral progeny through cleaving α-ketosidic linkage between the SA and an adjacent sugar residue [5].α-ketosidic linkage between the SA and an adjacent sugar residue [5].The HA and NA proteins are also highly immunogenic and antibodies targeting both glycoproteins can be isolated after natural infection or vaccination. Through binding to viral surface proteins HA and NA, antibodies can block the essential steps in the virus replication cycle, thereby limiting the spread of infection. Due to the host immune pressure and error-prone RNA polymerase, HA and NA are very plastic and display difference in antigenic properties. According to the antigenic difference, influenza A virus can divide into 18 HA (H1-H18) and 11 NA (N1-N11) subtypes [6]. According to the Weekly U.S. Influenza Surveillance Report released by CDC, H1N1(pdm09) and B/Victoria lineage viruses are equally dominant and responsible for the majority of death cases during the 2019-2020 influenza season [7].

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A multifunctional human monoclonal neutralizing antibody that targets a unique conserved epitope on influenza HA

Cited by 82 publications

References 71 publications

Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor binding head domains

Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor binding head domains

Engineered Recombinant Single Chain Variable Fragment of Monoclonal Antibody Provides Protection to Chickens Infected with H9N2 Avian Influenza

Influenza A Virus Antibodies with Antibody-Dependent Cellular Cytotoxicity Function

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