A potent broad-spectrum protective human monoclonal antibody crosslinking two haemagglutinin monomers of influenza A virus

Wu, Ying; Cho, MyungSam; Shore, D.A.; Song, Manki; Choi, Jung-ah; Jiang, Tao; Deng, Yong-Qiang; Bourgeois, Melissa; Almli, Lynn M.; Yang, Hua; Chen, Limei; Shi, Yi; Qi, J.; Li, An; Yi, Kye Sook; Chang, MinSeok; Bae, Jin Soo; Lee, Hyun-Joo; Shin, Ji‐Young; Stevens, James; Hong, SeoungSuh; Qin, Cheng‐Feng; Gao, George F.; Chang, Shin Jae; Donis, Ruben O.

doi:10.1038/ncomms8708

Cited by 126 publications

(132 citation statements)

References 58 publications

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“…Although light chains of this class contribute about one-third of the total buried surface area, analysis of antibodies of this class revealed light chain sequences to derive from diverse LV genes, with only KV3-11 appearing twice. Also, the recently reported HV1-18-derived group 1 and group 2-neutralizing antibody CT149 uses a Gln98 HC -x-x-Val100a HC motif with a 19 amino acid CDR H3 to bind the HA stem (Wu et al, 2015) and recognized HA in a manner highly similar to both 16.a.26 and 16.g.07. We tested the functional complementation for antibodies 16.a.26, 16.g.07, 54.a.39, 54.a.84, and CT149 from donors 16, 54, and SH-K1 (the source of antibody CT149).…”

Section: Resultsmentioning

confidence: 99%

Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses

Joyce

Wheatley

Thomas

et al. 2016

Cell

277

381

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Antibodies capable of neutralizing divergent influenza A viruses could form the basis of a universal vaccine. Here, from subjects enrolled in an H5N1 DNA/MIV-prime-boost influenza vaccine trial, we sorted hemagglutinin-cross reactive memory-B cells and identified three antibody classes, each capable of neutralizing diverse subtypes of group 1 and 2-influenza A viruses. Co-crystal structures with hemagglutinin revealed that each class utilized characteristic germline genes and convergent sequence motifs to recognize overlapping epitopes in the hemagglutinin stem. All six analyzed subjects had sequences from at least one multidonor class, and -in half the subjects- multidonor-class sequences were recovered from >40% of cross reactive-B cells. By contrast, these multidonor-class sequences were rare in published antibody datasets. Vaccination with a divergent hemagglutinin can thus increase the frequency of B cells encoding broad influenza A-neutralizing antibodies; we propose the sequence signature-quantified prevalence of these B cells as a metric to guide universal influenza A-immunization strategies.

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Section: Resultsmentioning

confidence: 99%

Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses

Joyce

Wheatley

Thomas

et al. 2016

Cell

277

381

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“…Each virus was cleared by 7 dpi, and mice survived the lethal challenge, while 90 to 100% of control IgG-treated animals succumbed to infection. The in vivo effectiveness of delayed treatment using group 1- and 2-targeting bnAbs, such as 39.29, 81.39, FI6, FI6v3, CT149, 045-051310-2B06, S6-B01, 07-5E01, 41-5D06, and 41-5E04, was also demonstrated in animal models (21, 22, 25, 28, 30). …”

Section: Discussionmentioning

confidence: 87%

“…This panel contained viruses collected from various geographic locations and included seasonal viruses, zoonotic viruses, HPAI A(H5N2) and A(H5N8) viruses, subtypes responsible for an unprecedented outbreak in poultry in the U.S., and virus variants resistant to one or both classes of FDA-approved anti-influenza drugs. The strength of this study is the direct testing of this diverse group of viruses using the same in vitro neutralization method, while previous studies on group 1- and 2-targeting MAbs only tested selected subtypes in the neutralization assay (21–25). In addition, conclusions of the reported subtype coverage were made based on the antibody binding to recombinant proteins or results from neutralization assays using pseudotyped viruses.…”

Section: Discussionmentioning

confidence: 99%

“…The EC 50 s determined in our study were similar to those reported for viruses tested with the parental MAb 81.39 (0.65 to 26.3 nM, corresponding to 0.10 to 4.11 μg/ml) (21). Several mechanisms of in vitro neutralization by MAbs were previously demonstrated, such as prevention of cleavage by cellular protease needed for HA maturation, interference with the fusion between viral and endosomal membranes via binding to a monomeric HA or cross-linking the neighboring HA molecules, and potential disruption of viral egress (22, 25, 43). Accessibility to the antibody epitope seems to be favored when HA molecules are expressed on the surface of infected cells rather than on the surface of the virion (22).…”

Section: Discussionmentioning

confidence: 99%

“…These MAbs are 39.29 and 81.39 (21); FI6v3 (22); CR9114 (23); PN-SIA-28 (24); CT149 (25); VIS410 (26, 27); 045-051310-2B06 and S6-B01 (28); 05-2G02 (29); 07-5E01, 41-5D06, and 41-5E04 (30); HV6-1+HD3-3, HV1-18+HD3-9, and HV1-18 (Q-x-x-V) (31); and MEDI8852 (32). Nonetheless, their antiviral activities against all known subtypes of influenza A viruses has not been completely characterized.…”

Section: Introductionmentioning

confidence: 99%

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Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins

Marjuki

Mishin

Chai³

et al. 2016

J Virol

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The pandemic threat posed by emerging zoonotic influenza A viruses necessitates development of antiviral agents effective against various antigenic subtypes. Human monoclonal antibody (hMAb) targeting the hemagglutinin (HA) stalk offers a promising approach to control influenza virus infections. Here, we investigated the ability of the hMAb 81.39a to inhibit in vitro replication of human and zoonotic viruses, representing 16 HA subtypes. The majority of viruses were effectively neutralized by 81.39a at a 50% effective concentration (EC50) of <0.01 to 4.9 μg/ml. Among group 2 HA viruses tested, a single A(H7N9) virus was not neutralized at 50 μg/ml; it contained HA2-Asp19Gly, an amino acid position previously associated with resistance to neutralization by the group 2 HA-neutralizing MAb CR8020. Notably, among group 1 HA viruses, H11-H13 and H16 subtypes were not neutralized at 50 μg/ml; they shared the substitution HA2-Asp19Asn/Ala. Conversely, H9 viruses harboring HA2-Asp19Ala were fully susceptible to neutralization. Therefore, amino acid variance at HA2-Asp19 has subtype-specific adverse effects on in vitro neutralization. Mice given a single injection (15 or 45 mg/kg of body weight) at 24 or 48 h after infection with recently emerged A(H5N2), A(H5N8), A(H6N1), or A(H7N9) viruses were protected from mortality and showed drastically reduced lung viral titers. Furthermore, 81.39a protected mice infected with A(H7N9) harboring HA2-Asp19Gly, although the antiviral effect was lessened. A(H1N1)pdm09-infected ferrets receiving a single dose (25 mg/kg) had reduced viral titers and showed less lung tissue injury, despite 24- to 72-h-delayed treatment. Taken together, this study provides experimental evidence for the therapeutic potential of 81.39a against diverse influenza A viruses. IMPORTANCE Zoonotic influenza viruses, such as A(H5N1) and A(H7N9) subtypes, have caused severe disease and deaths in humans, raising public health concerns. Development of novel anti-influenza therapeutics with a broad spectrum of activity against various subtypes is necessary to mitigate disease severity. Here, we demonstrate that the hemagglutinin (HA) stalk-targeting human monoclonal antibody 81.39a effectively neutralized the majority of influenza A viruses tested, representing 16 HA subtypes. Furthermore, delayed treatment with 81.39a significantly suppressed virus replication in the lungs, prevented dramatic body weight loss, and increased survival rates of mice infected with A(H5Nx), A(H6N1), or A(H7N9) viruses. When tested in ferrets, delayed 81.39a treatment reduced viral titers, particularly in the lower respiratory tract, and substantially alleviated disease symptoms associated with severe A(H1N1)pdm09 influenza. Collectively, our data demonstrated the effectiveness of 81.39a against both seasonal and emerging influenza A viruses.

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Glycosylation of Antigen-Specific Antibodies: Perspectives on Immunoglobulin G Glycosylation in Vaccination and Immunotherapy

Bharadwaj

Ackerman

2021

Experientia Supplementum

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A potent broad-spectrum protective human monoclonal antibody crosslinking two haemagglutinin monomers of influenza A virus

Cited by 126 publications

References 58 publications

Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses

Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses

Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins

Glycosylation of Antigen-Specific Antibodies: Perspectives on Immunoglobulin G Glycosylation in Vaccination and Immunotherapy

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