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Structure paper

TitleHuman monoclonal antibodies that target clade 2.3.4.4b H5N1 hemagglutinin.
Journal, issue, pagesNat Commun, Year 2025
Publish dateDec 13, 2025
AuthorsGarazi Peña Alzua / André Nicolás León / Temima Yellin / Disha Bhavsar / Madhumathi Loganathan / Kaitlyn Bushfield / Philip J M Brouwer / Alesandra J Rodriguez / Trushar Jeevan / Richard Webby / Christine Marizzi / Julianna Han / Andrew B Ward / J Andrew Duty / Florian Krammer /
PubMed AbstractThe highly pathogenic avian influenza H5N1 virus clade 2.3.4.4b has been spreading globally since 2022, causing mortality and morbidity in domestic and wild birds, as well as in mammals, which ...The highly pathogenic avian influenza H5N1 virus clade 2.3.4.4b has been spreading globally since 2022, causing mortality and morbidity in domestic and wild birds, as well as in mammals, which underscores its potential to cause a pandemic. Here, we generate a panel of anti-hemagglutinin (HA) human monoclonal antibodies (mAbs) against the H5 protein of clade 2.3.4.4b. To develop human chimeric antibodies, H2L2 Harbor Mice®, which express human immunoglobulin germline genes, were immunized with H5 and N1 recombinant proteins from A/mallard/New York/22-008760-007- original/2022 H5N1 virus. Through hybridoma technology, sixteen fully human mAbs are generated, most of which show cross-reactivity against H5 proteins from different clade 2.3.4.4 virus variants. Fourteen out of the sixteen mAbs neutralize the virus in vitro. The mAbs with the strongest hemagglutination inhibition activity also demonstrate greater neutralizing capacity and show increased protective effects in vivo when administered prophylactically or therapeutically in a murine H5N1 challenge model. Using cryo-electron microscopy, we identify a cross-clonotype conserved motif that bound a hydrophobic groove on the head domain of H5 HA. Akin to mAbs against severe acute respiratory syndrome coronavirus 2 during the coronavirus 2019 pandemic, these mAbs could serve as treatments in case of a widespread H5N1 epidemic or pandemic.
External linksNat Commun / PubMed:41390501
MethodsEM (single particle)
Resolution3.06 - 25.0 Å
Structure data

EMDB-48510: Cryo-EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 20D10 and CR9114
PDB-9mq1: Cryo-EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 20D10
Method: EM (single particle) / Resolution: 3.37 Å

EMDB-48511: Cryo-EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 12G1 and CR9114
PDB-9mq2: Cryo-EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 12G1
Method: EM (single particle) / Resolution: 3.06 Å

EMDB-48512: Cryo-EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 6G1, 1A1 and CR9114
PDB-9mq3: Cryo-EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 6G1
Method: EM (single particle) / Resolution: 3.22 Å

EMDB-48679: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 1A1
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48680: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 1H2
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48681: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 6G1
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48682: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 7G4
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48683: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 7G11
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48684: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 12C11
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48685: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 12G1
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48686: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 12G8
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48687: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 12G9
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48688: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 13E8
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48689: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 17C12
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48690: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 17E3
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48692: Negative stain EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fab 20D10
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-48693: A/Red-tailed hawk/New York/NYCVH 22-8477/2022 H5 in complex with monoclonal fab 1A1
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-48694: Negative stain map of A/Red-tailed hawk/New York/NYCVH 22-8477/2022 H5 in complex with monoclonal Fab 20D10
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-48695: Negative stain map of A/Red-tailed hawk/New York/NYCVH 22-8477/2022 H5 in complex with monoclonal Fab 6G1
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-48696: Negative stain map of A/Red-tailed hawk/New York/NYCVH 22-8477/2022 H5 in complex with monoclonal Fab 12G1
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-48822: Cryo-EM map of H5 HA (A/Jiangsu/NJ210/2023) in complex with monoclonal fabs 1A1, 6G1, and CR9114.
Method: EM (single particle) / Resolution: 3.47 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • influenza a virus
  • Mus musculus (house mouse)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / influenza / hemaglutinin / antibody-antigen complex / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / hemagglutinin / H5 / monoclonal / complex / fab complex / viral fusion protein

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