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Article: Properties and therapeutic efficacy of broadly reactive chimeric and humanized H5-specific monoclonal antibodies against H5N1 influenza viruses
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TitleProperties and therapeutic efficacy of broadly reactive chimeric and humanized H5-specific monoclonal antibodies against H5N1 influenza viruses
 
AuthorsZheng, Q1
Xia, L1
Wu, WL2
Zheng, Z1
Huo, Y1
Wu, J1
Liu, Y1
Yu, H1
Chen, Y1
Lau, SY2
Chen, H2
Luo, W1
Xia, N1
 
Issue Date2011
 
PublisherAmerican Society for Microbiology.
 
CitationAntimicrobial Agents And Chemotherapy, 2011, v. 55 n. 4, p. 1349-1357 [How to Cite?]
DOI: http://dx.doi.org/10.1128/AAC.01436-10
 
AbstractHighly pathogenic H5N1 virus infection causes severe disease and a high rate of fatality in humans. Development of humanized monoclonal antibodies may provide an efficient therapeutic regime for H5N1 virus infection. In the present study, broadly cross-reactive monoclonal antibodies (MAbs) derived from mice were humanized to minimize immunogenicity. One chimeric antibody (cAb) and seven humanized antibodies (hAbs) were constructed. These antibodies retained broad-spectrum reactivity to H5N1 viruses, binding to recombinant H5-subtype HA1 molecules expressed in CHO cells in a dose-dependent manner and exhibiting similar reactivities against antigenically distinct H5N1 viruses in hemagglutination inhibition (HI) assays. One humanized antibody, 37 hAb, showed HI and neutralization activities comparable to that of the parental murine antibody, 13D4 MAb, while the other six antibodies were less reactive to H5N1 viruses. Analysis of amino acid sequences in the variable region frameworks of the seven humanized antibodies found that Q5 and Y27 in the VH region are highly conserved murine residues. Comparison of the three-dimensional structures derived from the variable regions of MAbs 37 hAb, H1202-34, and 13D4 revealed that residue substitutions at sites 70 and 46 may be the major cause for the observed differences in binding affinity. Examination of the chimeric antibody and one of the humanized antibodies, 37 hAb, showed that both antibodies offered postinfection protection against lethal challenge with antigenically diverse H5N1 viruses in the mouse model. Chimeric and humanized antibodies which retain the broadly reactive and protective properties of murine H5-specific monoclonal antibodies have great potential for use in the treatment of human H5N1 infection. Copyright © 2011, American Society for Microbiology. All Rights Reserved.
 
ISSN0066-4804
2012 Impact Factor: 4.565
2012 SCImago Journal Rankings: 1.963
 
DOIhttp://dx.doi.org/10.1128/AAC.01436-10
 
PubMed Central IDPMC3067186
 
ISI Accession Number IDWOS:000288594600004
Funding AgencyGrant Number
Science and Technology Foundation of Fujian Province2009YZ0002
National Natural Science Foundation of China30901077
Ministry of Health2008ZX10004-006
University Grants CommitteeAoE/M-12/06
National Institutes of HealthHHSN2662007 00005C
Research Fund for the Control of Infectious Diseases of the Health, Welfare, and Food Bureau of the Hong Kong SAR
Funding Information:

This study was supported by the Key Project of the Science and Technology Foundation of Fujian Province (grant no. 2009YZ0002), the National Natural Science Foundation of China (grant no. 30901077), the Key Project of the Ministry of Health (grant no. 2008ZX10004-006), the Areas of Excellence Scheme of the University Grants Committee (grant AoE/M-12/06), the National Institutes of Health (NIAID contract HHSN2662007 00005C), and the Research Fund for the Control of Infectious Diseases of the Health, Welfare, and Food Bureau of the Hong Kong SAR).

 
ReferencesReferences in Scopus
 
GrantsControl of Pandemic and Inter-pandemic Influenza
 
DC FieldValue
dc.contributor.authorZheng, Q
 
dc.contributor.authorXia, L
 
dc.contributor.authorWu, WL
 
dc.contributor.authorZheng, Z
 
dc.contributor.authorHuo, Y
 
dc.contributor.authorWu, J
 
dc.contributor.authorLiu, Y
 
dc.contributor.authorYu, H
 
dc.contributor.authorChen, Y
 
dc.contributor.authorLau, SY
 
dc.contributor.authorChen, H
 
dc.contributor.authorLuo, W
 
dc.contributor.authorXia, N
 
dc.date.accessioned2011-10-28T02:45:35Z
 
dc.date.available2011-10-28T02:45:35Z
 
dc.date.issued2011
 
dc.description.abstractHighly pathogenic H5N1 virus infection causes severe disease and a high rate of fatality in humans. Development of humanized monoclonal antibodies may provide an efficient therapeutic regime for H5N1 virus infection. In the present study, broadly cross-reactive monoclonal antibodies (MAbs) derived from mice were humanized to minimize immunogenicity. One chimeric antibody (cAb) and seven humanized antibodies (hAbs) were constructed. These antibodies retained broad-spectrum reactivity to H5N1 viruses, binding to recombinant H5-subtype HA1 molecules expressed in CHO cells in a dose-dependent manner and exhibiting similar reactivities against antigenically distinct H5N1 viruses in hemagglutination inhibition (HI) assays. One humanized antibody, 37 hAb, showed HI and neutralization activities comparable to that of the parental murine antibody, 13D4 MAb, while the other six antibodies were less reactive to H5N1 viruses. Analysis of amino acid sequences in the variable region frameworks of the seven humanized antibodies found that Q5 and Y27 in the VH region are highly conserved murine residues. Comparison of the three-dimensional structures derived from the variable regions of MAbs 37 hAb, H1202-34, and 13D4 revealed that residue substitutions at sites 70 and 46 may be the major cause for the observed differences in binding affinity. Examination of the chimeric antibody and one of the humanized antibodies, 37 hAb, showed that both antibodies offered postinfection protection against lethal challenge with antigenically diverse H5N1 viruses in the mouse model. Chimeric and humanized antibodies which retain the broadly reactive and protective properties of murine H5-specific monoclonal antibodies have great potential for use in the treatment of human H5N1 infection. Copyright © 2011, American Society for Microbiology. All Rights Reserved.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationAntimicrobial Agents And Chemotherapy, 2011, v. 55 n. 4, p. 1349-1357 [How to Cite?]
DOI: http://dx.doi.org/10.1128/AAC.01436-10
 
dc.identifier.doihttp://dx.doi.org/10.1128/AAC.01436-10
 
dc.identifier.epage1357
 
dc.identifier.hkuros197190
 
dc.identifier.isiWOS:000288594600004
Funding AgencyGrant Number
Science and Technology Foundation of Fujian Province2009YZ0002
National Natural Science Foundation of China30901077
Ministry of Health2008ZX10004-006
University Grants CommitteeAoE/M-12/06
National Institutes of HealthHHSN2662007 00005C
Research Fund for the Control of Infectious Diseases of the Health, Welfare, and Food Bureau of the Hong Kong SAR
Funding Information:

This study was supported by the Key Project of the Science and Technology Foundation of Fujian Province (grant no. 2009YZ0002), the National Natural Science Foundation of China (grant no. 30901077), the Key Project of the Ministry of Health (grant no. 2008ZX10004-006), the Areas of Excellence Scheme of the University Grants Committee (grant AoE/M-12/06), the National Institutes of Health (NIAID contract HHSN2662007 00005C), and the Research Fund for the Control of Infectious Diseases of the Health, Welfare, and Food Bureau of the Hong Kong SAR).

 
dc.identifier.issn0066-4804
2012 Impact Factor: 4.565
2012 SCImago Journal Rankings: 1.963
 
dc.identifier.issue4
 
dc.identifier.pmcidPMC3067186
 
dc.identifier.pmid21245446
 
dc.identifier.scopuseid_2-s2.0-79953208049
 
dc.identifier.spage1349
 
dc.identifier.urihttp://hdl.handle.net/10722/142417
 
dc.identifier.volume55
 
dc.languageeng
 
dc.publisherAmerican Society for Microbiology.
 
dc.publisher.placeUnited States
 
dc.relation.ispartofAntimicrobial Agents and Chemotherapy
 
dc.relation.projectControl of Pandemic and Inter-pandemic Influenza
 
dc.relation.referencesReferences in Scopus
 
dc.rightsAntimicrobial Agents and Chemotherapy. Copyright © American Society for Microbiology.
 
dc.rightsCopyright © American Society for Microbiology, Antimicrobial Agents and Chemotherapy, 2011, v. 55 n. 4, p. 1349-1357
 
dc.subject.meshAntibodies, Monoclonal - chemistry - immunology - therapeutic use
 
dc.subject.meshAntibodies, Viral - chemistry - immunology - therapeutic use
 
dc.subject.meshCHO Cells
 
dc.subject.meshCricetinae
 
dc.subject.meshInfluenza A Virus, H5N1 Subtype - immunology
 
dc.titleProperties and therapeutic efficacy of broadly reactive chimeric and humanized H5-specific monoclonal antibodies against H5N1 influenza viruses
 
dc.typeArticle
 
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Author Affiliations
  1. Xiamen University
  2. The University of Hong Kong