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Structural basis of a potent human monoclonal antibody against Zika virus targeting a quaternary epitope.
Long F, Doyle M, Fernandez E, Miller AS, Klose T, Sevvana M, Bryan A, Davidson E, Doranz BJ, Kuhn RJ, Diamond MS, Crowe JE, Rossmann MG
(2019) Proc Natl Acad Sci U S A 116: 1591-1596
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cryoelectron Microscopy, Disease Models, Animal, Epitopes, Humans, Male, Mice, Mice, Inbred C57BL, Vaccination, Viral Envelope Proteins, Zika Virus, Zika Virus Infection
Show Abstract · Added March 31, 2019
Zika virus (ZIKV) is a major human pathogen and member of the genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-resolution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.
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A protective human monoclonal antibody targeting the West Nile virus E protein preferentially recognizes mature virions.
Goo L, Debbink K, Kose N, Sapparapu G, Doyle MP, Wessel AW, Richner JM, Burgomaster KE, Larman BC, Dowd KA, Diamond MS, Crowe JE, Pierson TC
(2019) Nat Microbiol 4: 71-77
MeSH Terms: Aedes, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cell Line, Cercopithecus aethiops, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Protein Domains, Vero Cells, Viral Envelope Proteins, West Nile Fever, West Nile Virus Vaccines, West Nile virus
Show Abstract · Added March 31, 2019
West Nile virus (WNV), a member of the Flavivirus genus, is a leading cause of viral encephalitis in the United States. The development of neutralizing antibodies against the flavivirus envelope (E) protein is critical for immunity and vaccine protection. Previously identified candidate therapeutic mouse and human neutralizing monoclonal antibodies (mAbs) target epitopes within the E domain III lateral ridge and the domain I-II hinge region, respectively. To explore the neutralizing antibody repertoire elicited by WNV infection for potential therapeutic application, we isolated ten mAbs from WNV-infected individuals. mAb WNV-86 neutralized WNV with a 50% inhibitory concentration of 2 ng ml, one of the most potently neutralizing flavivirus-specific antibodies ever isolated. WNV-86 targets an epitope in E domain II, and preferentially recognizes mature virions lacking an uncleaved form of the chaperone protein prM, unlike most flavivirus-specific antibodies. In vitro selection experiments revealed a neutralization escape mechanism involving a glycan addition to E domain II. Finally, a single dose of WNV-86 administered two days post-infection protected mice from lethal WNV challenge. This study identifies a highly potent human neutralizing mAb with therapeutic potential that targets an epitope preferentially displayed on mature virions.
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18 MeSH Terms
Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein.
Kim AS, Austin SK, Gardner CL, Zuiani A, Reed DS, Trobaugh DW, Sun C, Basore K, Williamson LE, Crowe JE, Slifka MK, Fremont DH, Klimstra WB, Diamond MS
(2019) Nat Microbiol 4: 187-197
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cercopithecus aethiops, Cricetinae, Encephalitis Virus, Eastern Equine, Encephalomyelitis, Equine, Epitope Mapping, Epitopes, Female, HEK293 Cells, Humans, Mice, Protein Domains, Vero Cells, Viral Envelope Proteins
Show Abstract · Added March 31, 2019
Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus with a high case mortality rate in humans. EEEV is a biodefence concern because of its potential for aerosol spread and the lack of existing countermeasures. Here, we identify a panel of 18 neutralizing murine monoclonal antibodies (mAbs) against the EEEV E2 glycoprotein, several of which have 'elite' activity with 50 and 99% effective inhibitory concentrations (EC and EC) of less than 10 and 100 ng ml, respectively. Alanine-scanning mutagenesis and neutralization escape mapping analysis revealed epitopes for these mAbs in domains A or B of the E2 glycoprotein. A majority of the neutralizing mAbs blocked infection at a post-attachment stage, with several inhibiting viral membrane fusion. Administration of one dose of anti-EEEV mAb protected mice from lethal subcutaneous or aerosol challenge. These experiments define the mechanistic basis for neutralization by protective anti-EEEV mAbs and suggest a path forward for treatment and vaccine design.
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17 MeSH Terms
Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection.
Kinchen VJ, Zahid MN, Flyak AI, Soliman MG, Learn GH, Wang S, Davidson E, Doranz BJ, Ray SC, Cox AL, Crowe JE, Bjorkman PJ, Shaw GM, Bailey JR
(2018) Cell Host Microbe 24: 717-730.e5
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibody Specificity, Base Sequence, Binding Sites, Cell Line, Cricetulus, Epitopes, Female, HEK293 Cells, HIV-1, Hepacivirus, Hepatitis C, Hepatitis C Antibodies, Humans, Immunologic Memory, Male, Models, Molecular, Mutagenesis, Site-Directed, Viral Envelope Proteins, Viral Load
Show Abstract · Added March 31, 2019
The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains. Acquisition of resistance to bNAbs by some autologous strains was accompanied by progressive loss of E2 protein function, and temporally associated with HCV clearance. These data demonstrate that bNAbs can mediate clearance of human HCV infection by neutralizing infecting strains and driving escaped viruses to an unfit state. These immunopathologic events distinguish HCV from HIV-1 and suggest that development of an HCV vaccine may be achievable.
Copyright © 2018 Elsevier Inc. All rights reserved.
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22 MeSH Terms
Reporting of immune checkpoint inhibitor-associated myocarditis - Authors' reply.
Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB
(2018) Lancet 392: 384-385
MeSH Terms: Antibodies, Monoclonal, Humans, Myocarditis, Programmed Cell Death 1 Receptor
Added October 1, 2018
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C Flux Analysis Reveals that Rebalancing Medium Amino Acid Composition can Reduce Ammonia Production while Preserving Central Carbon Metabolism of CHO Cell Cultures.
McAtee Pereira AG, Walther JL, Hollenbach M, Young JD
(2018) Biotechnol J 13: e1700518
MeSH Terms: Amino Acids, Ammonia, Animals, Antibodies, Monoclonal, CHO Cells, Carbon, Cricetulus, Culture Media, Glycosylation, Metabolic Flux Analysis, Recombinant Proteins
Show Abstract · Added March 14, 2018
C metabolic flux analysis (MFA) provides a rigorous approach to quantify intracellular metabolism of industrial cell lines. In this study, C MFA was used to characterize the metabolic response of Chinese hamster ovary (CHO) cells to a novel medium variant designed to reduce ammonia production. Ammonia inhibits growth and viability of CHO cell cultures, alters glycosylation of recombinant proteins, and enhances product degradation. Ammonia production was reduced by manipulating the amino acid composition of the culture medium; specifically, glutamine, glutamate, asparagine, aspartate, and serine levels were adjusted. Parallel C flux analysis experiments determined that, while ammonia production decreased by roughly 40%, CHO cell metabolic phenotype, growth, viability, and monoclonal antibody (mAb) titer were not significantly altered by the changes in media composition. This study illustrates how C flux analysis can be applied to assess the metabolic effects of media manipulations on mammalian cell cultures. The analysis revealed that adjusting the amino acid composition of CHO cell culture media can effectively reduce ammonia production while preserving fluxes throughout central carbon metabolism.
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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11 MeSH Terms
The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding.
King LB, Fusco ML, Flyak AI, Ilinykh PA, Huang K, Gunn B, Kirchdoerfer RN, Hastie KM, Sangha AK, Meiler J, Alter G, Bukreyev A, Crowe JE, Saphire EO
(2018) Cell Host Microbe 23: 101-109.e4
MeSH Terms: Agrobacterium tumefaciens, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Binding Sites, Carrier Proteins, Cell Line, Cercopithecus aethiops, Crystallography, X-Ray, Drosophila melanogaster, Humans, Marburgvirus, Membrane Glycoproteins, Receptors, Virus, Tobacco, Vero Cells, Viral Envelope Proteins, Viral Fusion Proteins, Virus Attachment
Show Abstract · Added March 17, 2018
Since their first identification 50 years ago, marburgviruses have emerged several times, with 83%-90% lethality in the largest outbreaks. Although no vaccines or therapeutics are available for human use, the human antibody MR191 provides complete protection in non-human primates when delivered several days after inoculation of a lethal marburgvirus dose. The detailed neutralization mechanism of MR191 remains outstanding. Here we present a 3.2 Å crystal structure of MR191 complexed with a trimeric marburgvirus surface glycoprotein (GP). MR191 neutralizes by occupying the conserved receptor-binding site and competing with the host receptor Niemann-Pick C1. The structure illuminates previously disordered regions of GP including the stalk, fusion loop, CXCC switch, and an N-terminal region of GP2 that wraps about the outside of GP1 to anchor a marburgvirus-specific "wing" antibody epitope. Virus escape mutations mapped far outside the MR191 receptor-binding site footprint suggest a role for these other regions in the GP quaternary structure.
Copyright © 2017 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Synergistic anti-HCV broadly neutralizing human monoclonal antibodies with independent mechanisms.
Mankowski MC, Kinchen VJ, Wasilewski LN, Flyak AI, Ray SC, Crowe JE, Bailey JR
(2018) Proc Natl Acad Sci U S A 115: E82-E91
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, HEK293 Cells, Hepacivirus, Hepatitis Antibodies, Hepatitis C, Humans, Viral Hepatitis Vaccines
Show Abstract · Added March 14, 2018
There is an urgent need for a vaccine to combat the hepatitis C virus (HCV) pandemic, and induction of broadly neutralizing monoclonal antibodies (bNAbs) against HCV is a major goal of vaccine development. Even within HCV genotype 1, no single bNAb effectively neutralizes all viral strains, so induction of multiple neutralizing monoclonal antibodies (NAbs) targeting distinct epitopes may be necessary for protective immunity. Therefore, identification of optimal NAb combinations and characterization of NAb interactions can guide vaccine development. We analyzed neutralization profiles of 12 human NAbs across diverse HCV strains, assigning the NAbs to two functionally distinct clusters. We then measured neutralizing breadth of 35 NAb combinations against genotype 1 isolates, with each combination including one NAb from each neutralization cluster. Many NAbs displayed complementary neutralizing breadth, forming combinations with greater neutralization across diverse strains than any individual bNAb. Remarkably, one of the most broadly neutralizing combinations of two NAbs, designated HEPC74/HEPC98, also displayed enhanced potency, with interactions matching the Bliss independence model, suggesting that these NAbs inhibit HCV infection through independent mechanisms. Subsequent experiments showed that HEPC74 primarily blocks HCV envelope protein binding to CD81, while HEPC98 primarily blocks binding to scavenger receptor B1 and heparan sulfate. Together, these data identify a critical vulnerability resulting from the reliance of HCV on multiple cell surface receptors, suggesting that vaccine induction of multiple NAbs with distinct neutralization profiles is likely to enhance the breadth and potency of the humoral immune response against HCV.
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8 MeSH Terms
A neutralizing antibody that blocks delivery of the enzymatic cargo of toxin TcdB into host cells.
Kroh HK, Chandrasekaran R, Zhang Z, Rosenthal K, Woods R, Jin X, Nyborg AC, Rainey GJ, Warrener P, Melnyk RA, Spiller BW, Lacy DB
(2018) J Biol Chem 293: 941-952
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, Bacterial Toxins, Caco-2 Cells, Clostridium difficile, Crystallography, X-Ray, Cytosol, Enterotoxins, Humans, Hydrogen-Ion Concentration, Microscopy, Electron, Rubidium, rac1 GTP-Binding Protein
Show Abstract · Added March 15, 2018
infection is the leading cause of hospital-acquired diarrhea and is mediated by the actions of two toxins, TcdA and TcdB. The toxins perturb host cell function through a multistep process of receptor binding, endocytosis, low pH-induced pore formation, and the translocation and delivery of an N-terminal glucosyltransferase domain that inactivates host GTPases. Infection studies with isogenic strains having defined toxin deletions have established TcdB as an important target for therapeutic development. Monoclonal antibodies that neutralize TcdB function have been shown to protect against infection in animal models and reduce recurrence in humans. Here, we report the mechanism of TcdB neutralization by PA41, a humanized monoclonal antibody capable of neutralizing TcdB from a diverse array of strains. Through a combination of structural, biochemical, and cell functional studies, involving X-ray crystallography and EM, we show that PA41 recognizes a single, highly conserved epitope on the TcdB glucosyltransferase domain and blocks productive translocation and delivery of the enzymatic cargo into the host cell. Our study reveals a unique mechanism of toxin neutralization by a monoclonal antibody, which involves targeting a process that is conserved across the large clostridial glucosylating toxins. The PA41 antibody described here provides a valuable tool for dissecting the mechanism of toxin pore formation and translocation across the endosomal membrane.
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13 MeSH Terms
Role of Non-local Interactions between CDR Loops in Binding Affinity of MR78 Antibody to Marburg Virus Glycoprotein.
Sangha AK, Dong J, Williamson L, Hashiguchi T, Saphire EO, Crowe JE, Meiler J
(2017) Structure 25: 1820-1828.e2
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, Antibody Affinity, Binding Sites, Antibody, Molecular Docking Simulation, Protein Binding, Viral Envelope Proteins
Show Abstract · Added March 14, 2018
An atomic-detail model of the Marburg virus glycoprotein in complex with a neutralizing human monoclonal antibody designated MR78 was constructed using Phenix.Rosetta starting from a 3.6Å crystallographic density map. The Asp at T6 in the HCDR3's bulged torso cannot form the canonical salt bridge as position T2 lacks an Arg or Lys residue. It instead engages in a hydrogen bond interaction with a Tyr contributed by the HCDR1 loop. This inter-CDR loop interaction stabilizes the bulged conformation needed for binding to the viral glycoprotein: a Tyr to Phe mutant displays a binding affinity reduced by a factor of at least 10. We found that 5% of a database of 465 million human antibody sequences has the same residues at T2 and T6 positions in HCDR3 and Tyr in HCDR1 that could potentially form this Asp-Tyr interaction, and that this interaction might contribute to a non-canonical bulged torso conformation.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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7 MeSH Terms